Next Article in Journal
Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms
Next Article in Special Issue
Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?
Previous Article in Journal
Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders
Previous Article in Special Issue
Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Connecting Dots between Mitochondrial Dysfunction and Depression

Mehtab Khan
Yann Baussan
1,2 and
Etienne Hebert-Chatelain
Department of Biology, University of Moncton, Moncton, NB E1A 3E9, Canada
Mitochondrial Signaling and Pathophysiology, University of Moncton, Moncton, NB E1A 3E9, Canada
Author to whom correspondence should be addressed.
Biomolecules 2023, 13(4), 695;
Submission received: 7 March 2023 / Revised: 10 April 2023 / Accepted: 12 April 2023 / Published: 20 April 2023
(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)


Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.

Graphical Abstract

1. Introduction

Mitochondria are highly dynamic organelles forming a network which spans throughout the cytosol [1]. Mitochondria are composed of four compartments: the outer and inner mitochondrial membranes (OMM and IMM, respectively), which are separated by the inter-membrane space (IMS), and the mitochondrial matrix surrounded by the IMM [2]. Mitochondrial morphology can be modulated by events of fusion and fission between individual organelles, which are crucial to maintain mitochondrial activity. Fission involves the GTPase dynamin-1-like protein (Drp1) and is required for mitochondrial quality control [3,4], while fusion is mainly driven by mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optic atrophy-1 (OPA1) [5,6,7,8], and allows the transfer of mitochondrial proteins, lipids, metabolites and mitochondrial DNA (mtDNA) between individual mitochondria. Mitochondria are the only organelles to possess their own genome, which mostly encodes components of the electron transport chain (ETC) [9]. One of the major roles of mitochondria is ATP production by the ETC and the ATP synthase. The ETC is composed of complexes I, II, III and IV embedded in special regions of the IMM named cristae and two mobile electron carriers, coenzyme Q and cytochrome c. Complexes I, III and IV generate a proton gradient across the IMM which is used by the ATP synthase to generate ATP. This process is called oxidative phosphorylation (OXPHOS). During this process, reactive oxygen species (ROS) are also generated as normal byproducts [10,11,12]. ROS can act as signaling cues but overaccumulation of ROS can lead to the oxidation of proteins and lipids, eventually resulting in autophagy, apoptosis, necrosis and inflammation [12,13,14]. Mitochondria also play an important role in Ca2+ clearance, lipid biogenesis, iron-sulfur (Fe-S) clustering and apoptosis [15,16].
Mitochondria are crucial for the brain’s physiology. The brain has among the highest energy needs in the human body and ATP production by mitochondria is thus essential to maintain the brain’s activity [17,18]. Mitochondria-derived ATP is critical for maintaining the Na+-K+-ATPase activity and, consequently, the membrane potential of neurons which is constantly disturbed by action potentials during a nerve impulse [19]. The capacity of mitochondria to buffer intracellular levels of Ca2+ is essential during synaptic transmission [19]. Thus, any defects of mitochondrial functions can lead to brain-related disorders, such as neurodegenerative diseases and neuropsychiatric disorders [20,21,22,23,24]. The glucose metabolism in different brain regions of patients with mood disorders appears disturbed [25,26,27,28]. In preclinical models of depression, the impaired expression of genes encoding mitochondrial proteins, lower activity of ETC components and mitochondrial metabolism, higher oxidative stress and oxidation of mitochondrial structures are all observed [29,30,31].
The aim of this review is to describe the extent of mitochondrial dysfunction observed in depression, from both clinical and preclinical perspectives.

2. Neurobiological Basis of Depression

Depression is a common neuropsychiatric disorder, which is widespread across the world, affecting more than 350 million people globally and leading to 1 million deaths by suicide annually [23,30,32]. Since 2008, the World Health Organization listed depression as the third largest cause of economic and disease burden, and it is expected to be ranked first by 2030 [33,34,35,36]. The traditional diagnosis of depression proposes two subtypes, (1) reactive/neurotic depression and (2) endogenous depression, which are based on the presence or absence of stress prior to the onset of depression, respectively [37]. The symptoms and severity vary among individuals, but can be characterized by persistent sadness, low mood or pleasure, decreased energy, altered appetite, deficits in sleep and cognitive capacities, weight loss or gain, decreased social functioning and increased suicidal probability [35,38,39]. Studies have shown that depression can be associated with other metabolic diseases, including cardiovascular and cerebrovascular impairments, autoimmune diseases, diabetes, cancer and a higher mortality rate [35,38,39,40]. Depression often coexists with other psychiatric conditions such as anxiety disorder [41].
Despite widespread preclinical and clinical research studies, the pathophysiology of depression remains poorly understood [42]. The monoamine hypothesis was one of the first dominant theories to explain the pathogenesis of depression. The disturbance of monoamines, such as serotonin and norepinephrine levels, in the brain disrupts the hypothalamus-pituitary-adrenal axis which controls the response to stress, which ultimately leads to depression [43,44,45]. Monoamine oxidase (MAO) is one of the main enzymes in monoamine metabolism and is a potential biomarker of mental disorders [46,47]. Altered MAO activity in the brain disrupts levels of monoamine neurotransmitters such as dopamine, noradrenaline, and serotonin. Defective MAO also impacts mitochondria: it can affect the structure of mitochondrial membranes by activating oxidative stress and increasing the toxic levels of aldehydes and ammonia [46,47]. However, treatment with monoamines seems to have little beneficial effect on the mood of patients. Only 40% of patients respond to treatment with monoamines, and depression-relapse is often observed, although the levels of monoamines are restored a few hours after injections [48,49].
The neurogenesis theory of depression suggests that stress decreases hippocampal neurogenesis, ultimately leading to depression [50]. Decreased hippocampal volume is observed in depressed patients, and decreased hippocampal neurogenesis and neuronal maturation are observed in mice and rats treated with corticosterone, a classic model of depression [30,50,51,52,53,54]. Interestingly, administration of antidepressants can rescue cell proliferation and survival within the hippocampus in animal models [55]. Reelin, an extracellular matrix protein which regulates adult hippocampal neurogenesis and dendritic spine plasticity could also be involved in the pathophysiology of depression. Indeed, injection of corticosterone in rats dampens the expression of reelin in the dentate gyrus of the hippocampus, which can be reversed by treatment with antidepressants [51,56,57].
Neurogenesis is also believed to be an important mechanism under physiological conditions and in brain repair after different injuries such as hypoxia and stroke [58,59]. In animal models of depression, hippocampal cell proliferation and neurogenesis is also altered [60]. Interestingly, the proliferation of neural precursor cells in the subgranular layer of hippocampus decreases, which can be restored by treatment with an antidepressant such as fluoxetine, tranylcypromine, reboxetine and rolipram [61]. Antidepressants, such as selective serotonin reuptake inhibitors and tianeptine, a modified tricyclic antidepressant, increase neurogenesis in the dentate gyrus of mice and non-human primates [55,60,62,63,64]. Similarly, staining with Ki67, which binds onto the proliferating cells, is reduced in the dentate gyrus of post-mortem brains of depressed patients [65,66]. In contrast, the treatment of a depressed patient with antidepressant increases the proliferation of the neural precursor cells in the dentate gyrus as compared to non-treated depressed patients or healthy controls [65]. Many studies have shown that during neuronal development, the mitochondrial biogenesis takes place at a faster rate as neuronal differentiation requires an increased mitochondrial genome and mitochondrial proteins [67,68,69,70,71]. Therefore, it is notable that mitochondrial dysfunction might have an important role in impaired adult hippocampal neurogenesis in depression. However, the neurogenesis hypothesis remains somewhat controversial since depression-like symptoms can occur even when the cell proliferation within the hippocampus is not decreased [72]. Also, antidepressants do not always increase hippocampal neurogenesis in animal models of depression [72,73,74]. In fact, the evidence suggests that depression and the efficacy of antidepressants may be more related to variations in dendritic plasticity and neuronal remodeling than neurogenesis [72,74,75]. Therefore, the role of neuroplasticity might be more important in the pathophysiology of depression. Neuroplasticity includes synaptic and non-synaptic plasticity in response to internal and external stimuli. Synaptic plasticity encompasses axonal and dendrite growth, synaptogenesis, and removal of defective connections between neurons. Mitochondria play an important role in neuroplasticity, and it is well known that impaired neuroplasticity due to mitochondrial stress leads to structural and functional impairment in different regions of the brain of depressed patients [23,76]. Overall, mitochondrial dysfunction might have important roles in impaired adult hippocampal neurogenesis and neuroplasticity in depression.
Depressed patients show pathological alterations in selective brain regions, including limbic (hippocampus, basal ganglia and amygdala) and cortical brain regions. These brain regions are involved in affective and cognitive impairments observed in depression [77]. Notably, neuroimaging studies by magnetic resonance imaging and positron emission tomography revealed metabolic alterations in depressed patients [78,79]. The brain regions metabolically impaired in depressed patients are (i) the cortical areas such as the prefrontal cortex, cingulate cortex, orbital frontal cortex and insula; (ii) the subcortical limbic regions such as the amygdala, hippocampus and the dorsomedial thalamus; and (iii) the basal ganglia and the brain stem region [78,80].

3. Models of Depression

The post-mortem brains of depressed patients are a crucial source of information for the pathophysiology of depression. However, it is important to consider that they are associated with important artefacts, such as increased oxidative stress that occurs during and after death [81,82]. The animal models of depression are a widely used alternative to the post-mortem brains of humans despite the fact that no animal model can perfectly mimic human depression due to its multifactorial pathophysiology [83,84]. Nonetheless, the animal models of depression helped improve our understanding of the pathophysiology of depression and its link with mitochondrial dysfunction (see Table 1). Three main criteria must be fulfilled to generate animal models of depression. First, they must have a phenotype similar to humans suffering from depression. Then, they must recapitulate the human physiopathology and should be sensitive to pharmacological or non-pharmacological treatments effective in humans [85,86,87]. The generation of animal models for depression mainly relies on stress exposure [88,89], and several protocols have been developed, based on numerous variables such as the nature of the stress, its severity and exposure parameters to induce and/or measure the depression-like phenotype [90].
The main protocols to induce a depression-like phenotype are exposure to chronic mild stress, social defeat stress and early-life stress [87,110,111,112,113]. These different protocols which are reviewed in [114] induce a depression-like phenotype, which can then be evaluated through various behavioral tests, including the forced swim test, the tail suspension test, the learned helplessness test and the sucrose preference test [111,115,116].

4. Mitochondrial Genetics and Depression

Mitochondria are the only organelles to have their own DNA known as mtDNA. The mtDNA encodes 13 polypeptides involved in OXPHOS, 12S and 16S ribosomal RNAs, as well as 22 unique transfer RNAs for protein synthesis [117,118,119]. Several observations link mtDNA and depression. The prevalence rate for depression is 54% in patients with mitochondrial diseases caused by specific mutations of mitochondrial genes [120]. One study revealed that 68% of patients with depression have mtDNA deletions, as compared to 36% of the control patients [121]. Likewise, there are significantly lower mtDNA copy numbers and increased mtDNA oxidative damage in the leukocytes of depressed patients as compared to the control individuals [122]. The resulting damaged mtDNA activates pro-inflammatory cytokines which leads to inflammation, a hallmark of depression [123,124]. Studies in mice and humans also showed that variation in the mtDNA copy numbers is associated with cognitive impairments, which are other common symptoms linked with depression [31,125,126]. The downregulation of DNA repair enzymes such as DNA polymerase gamma (POLG) and 8-oxoguanine-DNA glycosylase 1 (OGG1) in patients with depression suggest that this might be one of the mechanisms responsible for the low mtDNA copy number in depressed patients [127,128].
A number of specific mitochondrial genes have also been linked to depression [31]. Mitochondrial PCR array profiling analysis identified 16 genes differentially expressed in the dorsolateral prefrontal cortex of the post-mortem brains of depressed patients [129]. The identified genes were mainly related to oxidative stress and neuronal ATP levels [129]. Similarly, the ATP6V1B2, which encodes a subunit for the vacuolar proton pump ATPase, is upregulated and has shown effects on neurotransmission and receptor-mediated endocytosis that are involved in depression [31,130]. In summary, the defects of an abundance of mtDNA or mitochondrial gene expression support the idea that mitochondrial abnormalities may represent fundamental pathogenic mechanisms in depression.

5. Mitochondrial Proteome in Depression

In humans, 1500 different mitochondrial proteins are involved in mitochondrial dynamics, mtDNA maintenance, bioenergetics, mitophagy, import of proteins inside the organelle, and ion channels [131]. Many studies have demonstrated the involvement of the energy metabolism-related proteome in depression. The brains of depressed patients show altered levels of proteins involved in many metabolic pathways including OXPHOS, pyruvate metabolism and the tricarboxylic acid cycle [132]. A proteomic study on the post-mortem brains of depressed patients showed that 21% of mitochondrial proteins have altered levels [133,134]. Another work showed that 20 subunits of the ETC complexes were increased in the post-mortem human brains of depressed patients [81]. Similar findings were observed in animal models of depression. The congenic C57BL/6NTac mutant mouse model of depression shows dysregulation of metabolism and altered levels of OXPHOS protein in the hippocampus, which is the main brain region with reduced neuroplasticity in both human and mice models of depression [135,136]. Similarly, increased levels of ETC complex I and IV, cytochrome c and ATP synthase were also observed in the dorsolateral prefrontal, anterior cingulate and parieto-occipital cortices of depressed patients [81,137,138,139,140,141]. Carbonic anhydrase and aldolase c are also increased in the frontal cortex and the anterior cingulate cortex of depressed patients [137,142].
The antidepressant fluoxetine is part of the initial treatment for depression [143]. Fluoxetine seems to affect levels of cytosolic and mitochondrial proteins differently. In the cytosol, 23 proteins were upregulated whereas 60 were downregulated upon treatment with fluoxetine. In mitochondria, 60 proteins were upregulated and 3 were downregulated upon the same treatment [144], suggesting that this antidepressant could treat depression through its action on the metabolism-related proteome.
Overall, the mitochondrial proteome is affected in depressed patients, raising the possibility of developing mitochondrial biomarkers to follow the etiology of depression or to develop new treatments.

6. OXPHOS and ATP Production by Mitochondria in Depression

Mitochondria produce most of the ATP used by cells [81,145]. Preclinical and clinical studies have shown that, levels of neurometabolites, including ATP, are altered in depressed patients [122,123,124,146]. For instance, magnetic resonance spectroscopy has shown altered levels of phosphocreatine (PCr), N-acetyl-aspartate, adenosine diphosphate (ADP) and ATP in depressed patients [121,147]. Decreased mitochondrial ATP production was also observed in the muscles of depressed patients [121]. A decreased activity of ETC complexes I+III and II+III was also reported in the muscles of depressed patients compared to the control [121], suggesting that mitochondrial dysfunction linked to depression is not limited to the brain. Chronic mild stress can induce depression-like behavior, such as reduced sucrose preference and body weight, with the increased immobility time in the tail suspension test, leads to lower mitochondrial respiration, damaged mitochondrial ultrastructure, and mitochondrial depolarization in the hypothalamus, cortex and hippocampus in mice [102,148,149]. Interestingly, the antidepressant fluoxetine can restore sucrose preference, body weight, ATP synthesis and the respiratory control ratio (which is a quality index for OXPHOS) in the raphe nucleus in the chronic stress model in rodents [150]. Overall, these studies support the importance of appropriate ATP production by mitochondria in the pathophysiology of depression.

7. Oxidative Stress in Depression

Mitochondria are important sources of ROS, which play major roles in cellular physiology and signaling [151]. The reduction of O2 into H2O during OXPHOS can be incomplete and generate superoxide anions, which can then be converted into a hydroxyl radical and H2O2 [152]. ROS can be scavenged by the antioxidant system composed of catalase, superoxide dismutase, glutathione peroxidase and thioredoxin [153]. When the production of ROS exceeds the scavenging capacity of the antioxidant system, it can cause damage to proteins, lipids and DNA, including mtDNA [149,154]. Both preclinical and clinical studies reported mitochondrial dysfunctions linked to increased oxidative stress in depression [29,30,155,156,157]. Post-mortem analyses showed alterations of the complex I subunits NDUFV1, NDUFV2 and NDUFS1 and increased oxidative damage in the cerebellum of depressed patients [158]. A decreased level of antioxidant enzymes localized within mitochondria such as manganese superoxide dismutase was also reported in depressed patients [159,160]. Also, adult male rats stressed by immobilization for 21 days have reduced levels of the antioxidant glutathione with increased lipid peroxidation and levels of nitric oxide (NO) within the brain [161]. Decreased levels of glutathione and increased levels of superoxide, NO and lipid hydroperoxides are also observed upon olfactory bulbectomy, another model of depression in mice and rats [162,163]. Chronic mild stress during 40 days decreases sucrose preference, and inhibits the activity of ETC complexes I, III and IV in the cerebral cortex and cerebellum (Table 1) [101]. Interestingly, in the mouse model of high-anxiety, a common comorbidity of depression, the ETC components have reduced enzymatic activity, and increased ROS levels leading to lipid peroxidation and cell death [164]. Finally, the meta-analysis of 23 published studies suggests that markers of oxidative stress increase with the progression of depression [156,157]. Overall, numerous findings suggest that oxidative stress mediated by mitochondria dysfunction is linked to depression. Nevertheless, additional studies are required to elucidate and understand their mechanistic links with the symptoms of depression [165].

8. Calcium Homeostasis and Depression

Mitochondria play important roles in Ca2+ signaling as modulators, buffers and sensors of Ca2+ intracellular levels [166]. Ca2+ is imported through the OMM via the voltage-dependent anion channel and across the IMM through the mitochondrial Ca2+ uniporter [167]. The uptake of Ca2+ inside the mitochondrion has a significant impact on energy production, neuronal excitability and cellular death [168,169,170]. However, a Ca2+ overload within the mitochondria results in mitochondrial depolarization and the inhibition of OXPHOS, mitochondrial swelling, IMM remodeling, opening of the mitochondrial permeability transition pore, release of cytochrome c, activation of caspases and ultimately apoptosis [112,146,171,172]. The dysregulation of mitochondrial Ca2+ homeostasis appears to be involved in the pathophysiology of depression. Genome-wide association studies (GWAS) have identified Cacna1c as a candidate risk gene for multiple neuropsychiatric disorders, including bipolar disorder, schizophrenia and depression [173]. Cacna1c encodes the pore-forming α1C subunit of the L-type Ca2+ channel CaV1.2, which represents the major L-type voltage-gated calcium channel in the brain. CaV1.2 channels are critical modulators of many cellular processes involved in the progression of depression. CaV1.2-dependent gene expression plays an important role in neuronal plasticity, dendritic development and cell survival, suggesting that perturbation in CaV1.2 signaling might lead to depressive phenotypes [174,175,176]. The knockdown of CaV1.2 in rats induces an anti-depressive phenotype as assessed by the tail suspension, forced swim and sucrose preference tests, suggesting that loss of CaV1.2 regulates depressive-like behaviors [173,177,178,179]. Similarly, the knockdown of Cacna1c in neuronal HT22 cells, protects mitochondrial morphology, the mitochondrial membrane potential, ATP production and calcium homeostasis from glutamate excitotoxicity. The knockdown of Cacna1c also reduces the glutamate-induced increase of mitochondrial ROS production, intramitochondrial calcium influx and cell death in HT22 cells [180]. Thus, Ca2+ homeostasis appears to play an important role in many psychiatric disorders, including depression.

9. Inflammation and Mitochondria in Depression

Inflammation is one of the main processes involved in depression. Several studies have found dysregulation of both the innate and adaptive immune system in depressed patients [181,182]. Chronic psychological or physiological insults result in the activation of many inflammatory responses, including higher levels of circulating pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines [183]. Activation of the pro-inflammatory cytokines interferon-γ, interleukin (IL)-2, 1β, IL-6 and tumor necrosis factor-α (TNF-α) are observed in depressed patients [184,185,186]. Furthermore, reduction in the anti-inflammatory cytokines IL-4 and IL-10 were observed in depressed patients [187], indicating an imbalance between pro-inflammatory and anti-inflammatory cytokines.
Various protocols, including immobilization, physical restraint, psychological stress, open field stress and inescapable shock, known to induce depression-like phenotype in rodents, increase the levels of pro-inflammatory cytokines and NO within the brain and plasma [188,189,190]. Conversely, mice centrally injected with the pro-inflammatory cytokines TNF-α or IL-1β show depressive-like behaviors, such as increased immobility in the forced swim and tail suspension tests, as well as decreased sucrose preference [88,190]. Interestingly, TNF-α impairs the mitochondrial oxidative metabolism as a result of increased ROS production in animal models [191,192,193]. TNF-α has an inhibitory effect on ETC complex IV, leading to a decreased mitochondrial membrane potential and ATP levels [23,194]. Injection of lipopolysaccharide (LPS) induces a strong immune response and secretion of pro-inflammatory cytokines, which results in depression-like behavior in different tests, such as the sucrose preference, the tail suspension and the forced swim tests [195]. Interestingly, LPS-treated mice also have increased mitochondrial production of superoxide and lower ATP production with a blunted mitochondrial membrane potential in the hippocampus [196]. Administration of the antioxidant resveratrol reverses mitochondrial dysfunction and depression-like behaviors in LPS-treated mice [196]. LPS also reduces sucrose preference and increases the mRNA levels of subunits 1 and 3 of complex IV in the prefrontal cortex of rats [197]. Injection of dinitrobenzene sulfonic acid to mimic colitis and gut inflammation induces depression-like phenotype using the same behavioral tests, together with decreased levels of reduced glutathione and ATP, but increased levels of ROS in the hippocampus [198]. Overall, multiple findings support the hypothesis that inflammation and mitochondrial dysfunction are linked in the pathophysiology of depression.

10. Conclusions

The exact biological mechanisms underlying depression are still not perfectly elucidated. However, the evidence that is emerging suggests that mitochondrial dysfunction is involved in various psychiatric disorders, including depression. In this manuscript, we have highlighted the potential relevance of mitochondrial dysfunction in the pathophysiology of depression. In depression, mitochondrial dysfunction in terms of altered genetics and mtDNA, expression of mitochondrial proteins, OXPHOS and ATP production and oxidative stress can lead to apoptosis and inflammation, decreased neurogenesis and transmission among neural circuits in the cortex, hippocampus and striatum. Improving the mitochondrial functions could thus prevent or alleviate depression-like symptoms. More work focusing on the mechanistic links between mitochondrial dysfunction and depression may become an important avenue towards the development of new treatments against depression.

Author Contributions

Conceptualization, M.K., Y.B. and E.H.-C.; writing—original draft preparation, M.K., Y.B. and E.H.-C.; writing—review and editing, E.H.-C.; supervision, E.H.-C. All authors have read and agreed to the published version of the manuscript.


This work was funded through grants awarded to EHC by the Natural Sciences and Engineering Research Council of Canada (grant number RGPIN-2015-05880 and RGPIN-2022-03945), Canadian Health Research Institute (grant number 156238), Canada Research Chair program, New Brunswick Health Research Foundation and New Brunswick Innovation Foundation.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Roger, A.J.; Muñoz-Gómez, S.A.; Kamikawa, R. The Origin and Diversification of Mitochondria. Curr. Biol. CB 2017, 27, R1177–R1192. [Google Scholar] [CrossRef] [PubMed]
  2. Perkins, G.; Renken, C.; Martone, M.E.; Young, S.J.; Ellisman, M.; Frey, T. Electron Tomography of Neuronal Mitochondria: Three-Dimensional Structure and Organization of Cristae and Membrane Contacts. J. Struct. Biol. 1997, 119, 260–272. [Google Scholar] [CrossRef]
  3. Nagashima, S.; Tábara, L.-C.; Tilokani, L.; Paupe, V.; Anand, H.; Pogson, J.H.; Zunino, R.; McBride, H.M.; Prudent, J. Golgi-Derived PI(4)P-Containing Vesicles Drive Late Steps of Mitochondrial Division. Science 2020, 367, 1366–1371. [Google Scholar] [CrossRef] [PubMed]
  4. Collier, J.J.; Oláhová, M.; McWilliams, T.G.; Taylor, R.W. Mitochondrial Signalling and Homeostasis: From Cell Biology to Neurological Disease. Trends Neurosci. 2023, 46, 137–152. [Google Scholar] [CrossRef] [PubMed]
  5. Pernas, L.; Scorrano, L. Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function. Annu. Rev. Physiol. 2016, 78, 505–531. [Google Scholar] [CrossRef]
  6. Ge, Y.; Shi, X.; Boopathy, S.; McDonald, J.; Smith, A.W.; Chao, L.H. Two Forms of Opa1 Cooperate to Complete Fusion of the Mitochondrial Inner-Membrane. eLife 2020, 9, e50973. [Google Scholar] [CrossRef]
  7. Eura, Y.; Ishihara, N.; Yokota, S.; Mihara, K. Two Mitofusin Proteins, Mammalian Homologues of FZO, with Distinct Functions Are Both Required for Mitochondrial Fusion. J. Biochem. 2003, 134, 333–344. [Google Scholar] [CrossRef] [PubMed]
  8. Farmer, T.; Naslavsky, N.; Caplan, S. Tying Trafficking to Fusion and Fission at the Mighty Mitochondria. Traffic Cph. Den. 2018, 19, 569–577. [Google Scholar] [CrossRef] [PubMed]
  9. Gorman, G.S.; Chinnery, P.F.; DiMauro, S.; Hirano, M.; Koga, Y.; McFarland, R.; Suomalainen, A.; Thorburn, D.R.; Zeviani, M.; Turnbull, D.M. Mitochondrial Diseases. Nat. Rev. Dis. Primer 2016, 2, 16080. [Google Scholar] [CrossRef] [PubMed]
  10. Rb, H.; Ns, C. Mitochondrial Reactive Oxygen Species Regulate Cellular Signaling and Dictate Biological Outcomes. Trends Biochem. Sci. 2010, 35. [Google Scholar] [CrossRef]
  11. Angelova, P.R.; Abramov, A.Y. Functional Role of Mitochondrial Reactive Oxygen Species in Physiology. Free Radic. Biol. Med. 2016, 100, 81–85. [Google Scholar] [CrossRef]
  12. Cadenas, E.; Davies, K.J.A. Mitochondrial Free Radical Generation, Oxidative Stress, and Aging11This Article Is Dedicated to the Memory of Our Dear Friend, Colleague, and Mentor Lars Ernster (1920–1998), in Gratitude for All He Gave to Us. Free Radic. Biol. Med. 2000, 29, 222–230. [Google Scholar] [CrossRef]
  13. Kamata, H.; Honda, S.-I.; Maeda, S.; Chang, L.; Hirata, H.; Karin, M. Reactive Oxygen Species Promote TNFalpha-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases. Cell 2005, 120, 649–661. [Google Scholar] [CrossRef] [PubMed]
  14. Izeradjene, K.; Douglas, L.; Tillman, D.M.; Delaney, A.B.; Houghton, J.A. Reactive Oxygen Species Regulate Caspase Activation in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Resistant Human Colon Carcinoma Cell Lines. Cancer Res. 2005, 65, 7436–7445. [Google Scholar] [CrossRef]
  15. Rangaraju, V.; Lewis, T.L.; Hirabayashi, Y.; Bergami, M.; Motori, E.; Cartoni, R.; Kwon, S.-K.; Courchet, J. Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease. J. Neurosci. 2019, 39, 8200–8208. [Google Scholar] [CrossRef] [PubMed]
  16. Osellame, L.D.; Blacker, T.S.; Duchen, M.R. Cellular and Molecular Mechanisms of Mitochondrial Function. Best Pract. Res. Clin. Endocrinol. Metab. 2012, 26, 711–723. [Google Scholar] [CrossRef] [PubMed]
  17. Cardanho-Ramos, C.; Morais, V.A. Mitochondrial Biogenesis in Neurons: How and Where. Int. J. Mol. Sci. 2021, 22, 13059. [Google Scholar] [CrossRef] [PubMed]
  18. Werth, J.; Thayer, S. Mitochondria Buffer Physiological Calcium Loads in Cultured Rat Dorsal Root Ganglion Neurons. J. Neurosci. 1994, 14, 348–356. [Google Scholar] [CrossRef] [PubMed]
  19. Mattson, M.P.; Gleichmann, M.; Cheng, A. Mitochondria in Neuroplasticity and Neurological Disorders. Neuron 2008, 60, 748–766. [Google Scholar] [CrossRef]
  20. Gebara, E.; Zanoletti, O.; Ghosal, S.; Grosse, J.; Schneider, B.L.; Knott, G.; Astori, S.; Sandi, C. Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions. Biol. Psychiatry 2021, 89, 1033–1044. [Google Scholar] [CrossRef]
  21. Sr, S.; Mf, C. Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease. Prog. Neurobiol. 2013, 106, 17–32. [Google Scholar] [CrossRef]
  22. Ahmad, W.; Ijaz, B.; Shabbiri, K.; Ahmed, F.; Rehman, S. Oxidative Toxicity in Diabetes and Alzheimer’s Disease: Mechanisms behind ROS/RNS Generation. J. Biomed. Sci. 2017, 24, 76. [Google Scholar] [CrossRef] [PubMed]
  23. Bansal, Y.; Kuhad, A. Mitochondrial Dysfunction in Depression. Curr. Neuropharmacol. 2016, 14, 610–618. [Google Scholar] [CrossRef]
  24. Tripathi, A.; Scaini, G.; Barichello, T.; Quevedo, J.; Pillai, A. Mitophagy in Depression: Pathophysiology and Treatment Targets. Mitochondrion 2021, 61, 1–10. [Google Scholar] [CrossRef]
  25. Kimbrell, T.A.; Ketter, T.A.; George, M.S.; Little, J.T.; Benson, B.E.; Willis, M.W.; Herscovitch, P.; Post, R.M. Regional Cerebral Glucose Utilization in Patients with a Range of Severities of Unipolar Depression. Biol. Psychiatry 2002, 51, 237–252. [Google Scholar] [CrossRef]
  26. Drevets, W.C. Functional Anatomical Abnormalities in Limbic and Prefrontal Cortical Structures in Major Depression. In Progress in Brain Research; Cognition, emotion and autonomic responses: The integrative role of the prefrontal cortex and limbic structures; Elsevier: Amsterdam, The Netherlands, 2000; Volume 126, pp. 413–431. [Google Scholar]
  27. Mayberg, H.S.; Brannan, S.K.; Mahurin, R.K.; Jerabek, P.A.; Brickman, J.S.; Tekell, J.L.; Silva, J.A.; McGinnis, S.; Glass, T.G.; Martin, C.C.; et al. Cingulate Function in Depression: A Potential Predictor of Treatment Response. Neuroreport 1997, 8, 1057–1061. [Google Scholar] [CrossRef] [PubMed]
  28. Su, L.; Cai, Y.; Xu, Y.; Dutt, A.; Shi, S.; Bramon, E. Cerebral Metabolism in Major Depressive Disorder: A Voxel-Based Meta-Analysis of Positron Emission Tomography Studies. BMC Psychiatry 2014, 14, 321. [Google Scholar] [CrossRef] [PubMed]
  29. Liu, T.; Zhong, S.; Liao, X.; Chen, J.; He, T.; Lai, S.; Jia, Y. A Meta-Analysis of Oxidative Stress Markers in Depression. PLoS ONE 2015, 10, e0138904. [Google Scholar] [CrossRef]
  30. Allen, J.; Romay-Tallon, R.; Brymer, K.J.; Caruncho, H.J.; Kalynchuk, L.E. Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front. Neurosci. 2018, 12. [Google Scholar] [CrossRef]
  31. Petschner, P.; Gonda, X.; Baksa, D.; Eszlari, N.; Trivaks, M.; Juhasz, G.; Bagdy, G. Genes Linking Mitochondrial Function, Cognitive Impairment and Depression Are Associated with Endophenotypes Serving Precision Medicine. Neuroscience 2018, 370, 207–217. [Google Scholar] [CrossRef]
  32. Kessler, R.C.; McGonagle, K.A.; Zhao, S.; Nelson, C.B.; Hughes, M.; Eshleman, S.; Wittchen, H.-U.; Kendler, K.S. Lifetime and 12-Month Prevalence of DSM-III-R Psychiatric Disorders in the United States: Results From the National Comorbidity Survey. Arch. Gen. Psychiatry 1994, 51, 8–19. [Google Scholar] [CrossRef] [PubMed]
  33. Dadi, A.F.; Miller, E.R.; Bisetegn, T.A.; Mwanri, L. Global Burden of Antenatal Depression and Its Association with Adverse Birth Outcomes: An Umbrella Review. BMC Public Health 2020, 20, 173. [Google Scholar] [CrossRef]
  34. Zhu, S.; Zhao, L.; Fan, Y.; Lv, Q.; Wu, K.; Lang, X.; Li, Z.; Yi, Z.; Geng, D. Interaction between TNF-α and Oxidative Stress Status in First-Episode Drug-Naïve Schizophrenia. Psychoneuroendocrinology 2020, 114, 104595. [Google Scholar] [CrossRef]
  35. The Neurobiology of Depression. Available online: (accessed on 22 December 2022).
  36. Li, Z.; Ruan, M.; Chen, J.; Fang, Y. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci. Bull. 2021, 37, 863–880. [Google Scholar] [CrossRef] [PubMed]
  37. Malki, K.; Keers, R.; Tosto, M.G.; Lourdusamy, A.; Carboni, L.; Domenici, E.; Uher, R.; McGuffin, P.; Schalkwyk, L.C. The Endogenous and Reactive Depression Subtypes Revisited: Integrative Animal and Human Studies Implicate Multiple Distinct Molecular Mechanisms Underlying Major Depressive Disorder. BMC Med. 2014, 12, 73. [Google Scholar] [CrossRef] [PubMed]
  38. Konttinen, H.; van Strien, T.; Männistö, S.; Jousilahti, P.; Haukkala, A. Depression, Emotional Eating and Long-Term Weight Changes: A Population-Based Prospective Study. Int. J. Behav. Nutr. Phys. Act. 2019, 16, 28. [Google Scholar] [CrossRef]
  39. Karabatsiakis, A.; Schönfeldt-Lecuona, C. Depression, Mitochondrial Bioenergetics, and Electroconvulsive Therapy: A New Approach towards Personalized Medicine in Psychiatric Treatment - a Short Review and Current Perspective. Transl. Psychiatry 2020, 10, 1–9. [Google Scholar] [CrossRef]
  40. Qiu, W.; Cai, X.; Zheng, C.; Qiu, S.; Ke, H.; Huang, Y. Update on the Relationship Between Depression and Neuroendocrine Metabolism. Front. Neurosci. 2021, 15. [Google Scholar] [CrossRef] [PubMed]
  41. Kessler, R.C.; Nelson, C.B.; McGonagle, K.A.; Liu, J.; Swartz, M.; Blazer, D.G. Comorbidity of DSM-III-R Major Depressive Disorder in the General Population: Results from the US National Comorbidity Survey. Br. J. Psychiatry. Suppl. 1996, 168, 17–30. [Google Scholar] [CrossRef]
  42. Kalia, M. Neurobiological Basis of Depression: An Update. Metabolism 2005, 54, 24–27. [Google Scholar] [CrossRef]
  43. Aboul-Fotouh, S. Chronic Treatment with Coenzyme Q10 Reverses Restraint Stress-Induced Anhedonia and Enhances Brain Mitochondrial Respiratory Chain and Creatine Kinase Activities in Rats. Behav. Pharmacol. 2013, 24, 552. [Google Scholar] [CrossRef]
  44. Maes, M.; Fišar, Z.; Medina, M.; Scapagnini, G.; Nowak, G.; Berk, M. New Drug Targets in Depression: Inflammatory, Cell-Mediated Immune, Oxidative and Nitrosative Stress, Mitochondrial, Antioxidant, and Neuroprogressive Pathways. And New Drug Candidates—Nrf2 Activators and GSK-3 Inhibitors. Inflammopharmacology 2012, 20, 127–150. [Google Scholar] [CrossRef]
  45. Iwamoto, K.; Bundo, M.; Kato, T. Altered Expression of Mitochondria-Related Genes in Postmortem Brains of Patients with Bipolar Disorder or Schizophrenia, as Revealed by Large-Scale DNA Microarray Analysis. Hum. Mol. Genet. 2005, 14, 241–253. [Google Scholar] [CrossRef]
  46. Uzbekov, M.G. Monoamine Oxidase as a Potential Biomarker of the Efficacy of Treatment of Mental Disorders. Biochem. Mosc. 2021, 86, 773–783. [Google Scholar] [CrossRef] [PubMed]
  47. Caruso, G.; Benatti, C.; Blom, J.M.C.; Caraci, F.; Tascedda, F. The Many Faces of Mitochondrial Dysfunction in Depression: From Pathology to Treatment. Front. Pharmacol. 2019, 10, 995. [Google Scholar] [CrossRef] [PubMed]
  48. Thase, M.E. Preventing Relapse and Recurrence of Depression: A Brief Review of Therapeutic Options. CNS Spectr. 2006, 11, 12–21. [Google Scholar] [CrossRef]
  49. Trivedi, M.H.; Rush, A.J.; Wisniewski, S.R.; Nierenberg, A.A.; Warden, D.; Ritz, L.; Norquist, G.; Howland, R.H.; Lebowitz, B.; McGrath, P.J.; et al. Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Am. J. Psychiatry 2006, 163, 28–40. [Google Scholar] [CrossRef] [PubMed]
  50. Jacobs, B.L.; van Praag, H.; Gage, F.H. Depression and the Birth and Death of Brain Cells: The Turnover of Neurons in the Hippocampus Might Help to Explain the Onset of and Recovery from Clinical Depression. Am. Sci. 2000, 88, 340–345. [Google Scholar] [CrossRef]
  51. Fenton, E.Y.; Fournier, N.M.; Lussier, A.L.; Romay-Tallon, R.; Caruncho, H.J.; Kalynchuk, L.E. Imipramine Protects against the Deleterious Effects of Chronic Corticosterone on Depression-like Behavior, Hippocampal Reelin Expression, and Neuronal Maturation. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015, 60, 52–59. [Google Scholar] [CrossRef]
  52. Schoenfeld, T.J.; Cameron, H.A. Adult Neurogenesis and Mental Illness. Neuropsychopharmacology 2015, 40, 113–128. [Google Scholar] [CrossRef]
  53. Brummelte, S.; Galea, L.A.M. Chronic High Corticosterone Reduces Neurogenesis in the Dentate Gyrus of Adult Male and Female Rats. Neuroscience 2010, 168, 680–690. [Google Scholar] [CrossRef]
  54. Campbell, S.; Marriott, M.; Nahmias, C.; MacQueen, G.M. Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis. Am. J. Psychiatry 2004, 161, 598–607. [Google Scholar] [CrossRef]
  55. Santarelli, L.; Saxe, M.; Gross, C.; Surget, A.; Battaglia, F.; Dulawa, S.; Weisstaub, N.; Lee, J.; Duman, R.; Arancio, O.; et al. Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants. Science 2003, 301, 805–809. [Google Scholar] [CrossRef]
  56. Lussier, A.L.; Caruncho, H.J.; Kalynchuk, L.E. Repeated Exposure to Corticosterone, but Not Restraint, Decreases the Number of Reelin-Positive Cells in the Adult Rat Hippocampus. Neurosci. Lett. 2009, 460, 170–174. [Google Scholar] [CrossRef] [PubMed]
  57. Pujadas, L.; Gruart, A.; Bosch, C.; Delgado, L.; Teixeira, C.M.; Rossi, D.; Lecea, L.d.; Martínez, A.; Delgado-García, J.M.; Soriano, E. Reelin Regulates Postnatal Neurogenesis and Enhances Spine Hypertrophy and Long-Term Potentiation. J. Neurosci. 2010, 30, 4636–4649. [Google Scholar] [CrossRef]
  58. Kitamura, T.; Saitoh, Y.; Takashima, N.; Murayama, A.; Niibori, Y.; Ageta, H.; Sekiguchi, M.; Sugiyama, H.; Inokuchi, K. Adult Neurogenesis Modulates the Hippocampus-Dependent Period of Associative Fear Memory. Cell 2009, 139, 814–827. [Google Scholar] [CrossRef] [PubMed]
  59. Hayashi, Y.; Jinnou, H.; Sawamoto, K.; Hitoshi, S. Adult Neurogenesis and Its Role in Brain Injury and Psychiatric Diseases. J. Neurochem. 2018, 147, 584–594. [Google Scholar] [CrossRef]
  60. Malberg, J.E. Implications of Adult Hippocampal Neurogenesis in Antidepressant Action. J. Psychiatry Neurosci. JPN 2004, 29, 196–205. [Google Scholar] [PubMed]
  61. Czéh, B.; Michaelis, T.; Watanabe, T.; Frahm, J.; de Biurrun, G.; van Kampen, M.; Bartolomucci, A.; Fuchs, E. Stress-Induced Changes in Cerebral Metabolites, Hippocampal Volume, and Cell Proliferation Are Prevented by Antidepressant Treatment with Tianeptine. Proc. Natl. Acad. Sci. USA 2001, 98, 12796–12801. [Google Scholar] [CrossRef]
  62. Perera, T.D.; Coplan, J.D.; Lisanby, S.H.; Lipira, C.M.; Arif, M.; Carpio, C.; Spitzer, G.; Santarelli, L.; Scharf, B.; Hen, R.; et al. Antidepressant-Induced Neurogenesis in the Hippocampus of Adult Nonhuman Primates. J. Neurosci. Off. J. Soc. Neurosci. 2007, 27, 4894–4901. [Google Scholar] [CrossRef]
  63. Hitoshi, S.; Maruta, N.; Higashi, M.; Kumar, A.; Kato, N.; Ikenaka, K. Antidepressant Drugs Reverse the Loss of Adult Neural Stem Cells Following Chronic Stress. J. Neurosci. Res. 2007, 85, 3574–3585. [Google Scholar] [CrossRef]
  64. Duman, R.S.; Malberg, J.; Nakagawa, S. Regulation of Adult Neurogenesis by Psychotropic Drugs and Stress. J. Pharmacol. Exp. Ther. 2001, 299, 401–407. [Google Scholar] [PubMed]
  65. Boldrini, M.; Underwood, M.D.; Hen, R.; Rosoklija, G.B.; Dwork, A.J.; John Mann, J.; Arango, V. Antidepressants Increase Neural Progenitor Cells in the Human Hippocampus. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2009, 34, 2376–2389. [Google Scholar] [CrossRef]
  66. Reif, A.; Fritzen, S.; Finger, M.; Strobel, A.; Lauer, M.; Schmitt, A.; Lesch, K.-P. Neural Stem Cell Proliferation Is Decreased in Schizophrenia, but Not in Depression. Mol. Psychiatry 2006, 11, 514–522. [Google Scholar] [CrossRef]
  67. Kirby, D.M.; Rennie, K.J.; Smulders-Srinivasan, T.K.; Acin-Perez, R.; Whittington, M.; Enriquez, J.-A.; Trevelyan, A.J.; Turnbull, D.M.; Lightowlers, R.N. Transmitochondrial Embryonic Stem Cells Containing Pathogenic MtDNA Mutations Are Compromised in Neuronal Differentiation. Cell Prolif. 2009, 42, 413–424. [Google Scholar] [CrossRef] [PubMed]
  68. Calingasan, N.Y.; Ho, D.J.; Wille, E.J.; Campagna, M.V.; Ruan, J.; Dumont, M.; Yang, L.; Shi, Q.; Gibson, G.E.; Beal, M.F. Influence of Mitochondrial Enzyme Deficiency on Adult Neurogenesis in Mouse Models of Neurodegenerative Diseases. Neuroscience 2008, 153, 986–996. [Google Scholar] [CrossRef] [PubMed]
  69. Baxter, K.K.; Uittenbogaard, M.; Yoon, J.; Chiaramello, A. The Neurogenic Basic Helix-Loop-Helix Transcription Factor NeuroD6 Concomitantly Increases Mitochondrial Mass and Regulates Cytoskeletal Organization in the Early Stages of Neuronal Differentiation. ASN Neuro 2009, 1, AN20090036. [Google Scholar] [CrossRef]
  70. Cuperfain, A.B.; Zhang, Z.L.; Kennedy, J.L.; Gonçalves, V.F. The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease. Complex Psychiatry 2018, 4, 52–69. [Google Scholar] [CrossRef]
  71. Kasahara, T.; Kato, T. What Can Mitochondrial DNA Analysis Tell Us About Mood Disorders? Biol. Psychiatry 2018, 83, 731–738. [Google Scholar] [CrossRef]
  72. Bessa, J.M.; Ferreira, D.; Melo, I.; Marques, F.; Cerqueira, J.J.; Palha, J.A.; Almeida, O.F.X.; Sousa, N. The Mood-Improving Actions of Antidepressants Do Not Depend on Neurogenesis but Are Associated with Neuronal Remodeling. Mol. Psychiatry 2009, 14, 764–773. [Google Scholar] [CrossRef]
  73. David, D.J.; Samuels, B.A.; Rainer, Q.; Wang, J.-W.; Marsteller, D.; Mendez, I.; Drew, M.; Craig, D.A.; Guiard, B.P.; Guilloux, J.-P.; et al. Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression. Neuron 2009, 62, 479–493. [Google Scholar] [CrossRef]
  74. Surget, A.; Saxe, M.; Leman, S.; Ibarguen-Vargas, Y.; Chalon, S.; Griebel, G.; Hen, R.; Belzung, C. Drug-Dependent Requirement of Hippocampal Neurogenesis in a Model of Depression and of Antidepressant Reversal. Biol. Psychiatry 2008, 64, 293–301. [Google Scholar] [CrossRef]
  75. Lussier, A.L.; Lebedeva, K.; Fenton, E.Y.; Guskjolen, A.; Caruncho, H.J.; Kalynchuk, L.E. The Progressive Development of Depression-like Behavior in Corticosterone-Treated Rats Is Paralleled by Slowed Granule Cell Maturation and Decreased Reelin Expression in the Adult Dentate Gyrus. Neuropharmacology 2013, 71, 174–183. [Google Scholar] [CrossRef] [PubMed]
  76. Sheline, Y.I.; Gado, M.H.; Kraemer, H.C. Untreated Depression and Hippocampal Volume Loss. Am. J. Psychiatry 2003, 160, 1516–1518. [Google Scholar] [CrossRef] [PubMed]
  77. Manji, H.K.; Drevets, W.C.; Charney, D.S. The Cellular Neurobiology of Depression. Nat. Med. 2001, 7, 541–547. [Google Scholar] [CrossRef]
  78. Zhang, F.; Peng, W.; Sweeney, J.A.; Jia, Z.; Gong, Q. Brain Structure Alterations in Depression: Psychoradiological Evidence. CNS Neurosci. Ther. 2018, 24, 994–1003. [Google Scholar] [CrossRef] [PubMed]
  79. Spellman, T.; Liston, C. Toward Circuit Mechanisms of Pathophysiology in Depression. Am. J. Psychiatry 2020, 177, 381–390. [Google Scholar] [CrossRef] [PubMed]
  80. Pandya, M.; Altinay, M.; Malone, D.A.; Anand, A. Where in the Brain Is Depression? Curr. Psychiatry Rep. 2012, 14, 634–642. [Google Scholar] [CrossRef]
  81. Martins-de-Souza, D.; Guest, P.C.; Harris, L.W.; Vanattou-Saifoudine, N.; Webster, M.J.; Rahmoune, H.; Bahn, S. Identification of Proteomic Signatures Associated with Depression and Psychotic Depression in Post-Mortem Brains from Major Depression Patients. Transl. Psychiatry 2012, 2, e87. [Google Scholar] [CrossRef]
  82. Hardy, J.A.; Dodd, P.R. Metabolic and Functional Studies on Post-Mortem Human Brain. Neurochem. Int. 1983, 5, 253–266. [Google Scholar] [CrossRef]
  83. Fuchs, E.; Flügge, G. Experimental Animal Models for the Simulation of Depression and Anxiety. Dialogues Clin. Neurosci. 2006, 8, 323–333. [Google Scholar] [CrossRef]
  84. Czéh, B.; Simon, M. Benefits of Animal Models to Understand the Pathophysiology of Depressive Disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 2021, 106, 110049. [Google Scholar] [CrossRef] [PubMed]
  85. Vollmayr, B.; Mahlstedt, M.M.; Henn, F.A. Neurogenesis and Depression: What Animal Models Tell Us about the Link. Eur. Arch. Psychiatry Clin. Neurosci. 2007, 257, 300–303. [Google Scholar] [CrossRef] [PubMed]
  86. Anisman, H.; Matheson, K. Stress, Depression, and Anhedonia: Caveats Concerning Animal Models. Neurosci. Biobehav. Rev. 2005, 29, 525–546. [Google Scholar] [CrossRef] [PubMed]
  87. Willner, P.; Mitchell, P.J. The Validity of Animal Models of Predisposition to Depression. Behav. Pharmacol. 2002, 13, 169–188. [Google Scholar] [CrossRef] [PubMed]
  88. Klinedinst, N.J.; Regenold, W.T. A Mitochondrial Bioenergetic Basis of Depression. J. Bioenerg. Biomembr. 2015, 47, 155–171. [Google Scholar] [CrossRef] [PubMed]
  89. Nestler, E.J.; Hyman, S.E. Animal Models of Neuropsychiatric Disorders. Nat. Neurosci. 2010, 13, 1161–1169. [Google Scholar] [CrossRef] [PubMed]
  90. Duman, C.H. Models of Depression. Vitam. Horm. 2010, 82, 1–21. [Google Scholar] [CrossRef]
  91. Mairesse, J.; Vercoutter-Edouart, A.S.; Marrocco, J.; Zuena, A.R.; Giovine, A.; Nicoletti, F.; Michalski, J.C.; Maccari, S.; Morley-Fletcher, S. Proteomic Characterization in the Hippocampus of Prenatally Stressed Rats. J. Proteomics 2012, 75, 1764–1770. [Google Scholar] [CrossRef]
  92. Marais, L.; Hattingh, S.M.; Stein, D.J.; Daniels, W.M.U. A Proteomic Analysis of the Ventral Hippocampus of Rats Subjected to Maternal Separation and Escitalopram Treatment. Metab. Brain Dis. 2009, 24, 569–586. [Google Scholar] [CrossRef]
  93. Marais, L.; van Rensburg, S.J.; van Zyl, J.M.; Stein, D.J.; Daniels, W.M.U. Maternal Separation of Rat Pups Increases the Risk of Developing Depressive-like Behavior after Subsequent Chronic Stress by Altering Corticosterone and Neurotrophin Levels in the Hippocampus. Neurosci. Res. 2008, 61, 106–112. [Google Scholar] [CrossRef]
  94. Piubelli, C.; Carboni, L.; Becchi, S.; Mathé, A.A.; Domenici, E. Regulation of Cytoskeleton Machinery, Neurogenesis and Energy Metabolism Pathways in a Rat Gene-Environment Model of Depression Revealed by Proteomic Analysis. Neuroscience 2011, 176, 349–380. [Google Scholar] [CrossRef]
  95. Yadid, G.; Nakash, R.; Deri, I.; Tamar, G.; Kinor, N.; Gispan, I.; Zangen, A. Elucidation of the Neurobiology of Depression: Insights from a Novel Genetic Animal Model. Prog. Neurobiol. 2000, 62, 353–378. [Google Scholar] [CrossRef] [PubMed]
  96. Malki, K.; Campbell, J.; Davies, M.; Keers, R.; Uher, R.; Ward, M.; Paya-Cano, J.; Aitchinson, K.J.; Binder, E.; Sluyter, F.; et al. Pharmacoproteomic Investigation into Antidepressant Response in Two Mouse Inbred Strains. Proteomics 2012, 12, 2355–2365. [Google Scholar] [CrossRef] [PubMed]
  97. Bisgaard, C.F.; Jayatissa, M.N.; Enghild, J.J.; Sanchéz, C.; Artemychyn, R.; Wiborg, O. Proteomic Investigation of the Ventral Rat Hippocampus Links DRP-2 to Escitalopram Treatment Resistance and SNAP to Stress Resilience in the Chronic Mild Stress Model of Depression. J. Mol. Neurosci. MN 2007, 32, 132–144. [Google Scholar] [CrossRef] [PubMed]
  98. Bisgaard, C.F.; Bak, S.; Christensen, T.; Jensen, O.N.; Enghild, J.J.; Wiborg, O. Vesicular Signalling and Immune Modulation as Hedonic Fingerprints: Proteomic Profiling in the Chronic Mild Stress Depression Model. J. Psychopharmacol. Oxf. Engl. 2012, 26, 1569–1583. [Google Scholar] [CrossRef]
  99. Henningsen, K.; Palmfeldt, J.; Christiansen, S.; Baiges, I.; Bak, S.; Jensen, O.N.; Gregersen, N.; Wiborg, O. Candidate Hippocampal Biomarkers of Susceptibility and Resilience to Stress in a Rat Model of Depression. Mol. Cell. Proteomics MCP 2012, 11, M111.016428. [Google Scholar] [CrossRef]
  100. Kedracka-Krok, S.; Fic, E.; Jankowska, U.; Jaciuk, M.; Gruca, P.; Papp, M.; Kusmider, M.; Solich, J.; Debski, J.; Dadlez, M.; et al. Effect of Chronic Mild Stress and Imipramine on the Proteome of the Rat Dentate Gyrus. J. Neurochem. 2010, 113, 848–859. [Google Scholar] [CrossRef] [PubMed]
  101. Rezin, G.T.; Cardoso, M.R.; Gonçalves, C.L.; Scaini, G.; Fraga, D.B.; Riegel, R.E.; Comim, C.M.; Quevedo, J.; Streck, E.L. Inhibition of Mitochondrial Respiratory Chain in Brain of Rats Subjected to an Experimental Model of Depression. Neurochem. Int. 2008, 53, 395–400. [Google Scholar] [CrossRef] [PubMed]
  102. Gong, Y.; Chai, Y.; Ding, J.-H.; Sun, X.-L.; Hu, G. Chronic Mild Stress Damages Mitochondrial Ultrastructure and Function in Mouse Brain. Neurosci. Lett. 2011, 488, 76–80. [Google Scholar] [CrossRef]
  103. Mu, J.; Xie, P.; Yang, Z.-S.; Yang, D.-L.; Lv, F.-J.; Luo, T.-Y.; Li, Y. Neurogenesis and Major Depression: Implications from Proteomic Analyses of Hippocampal Proteins in a Rat Depression Model. Neurosci. Lett. 2007, 416, 252–256. [Google Scholar] [CrossRef]
  104. Yang, Y.; Yang, D.; Tang, G.; Zhou, C.; Cheng, K.; Zhou, J.; Wu, B.; Peng, Y.; Liu, C.; Zhan, Y.; et al. Proteomics Reveals Energy and Glutathione Metabolic Dysregulation in the Prefrontal Cortex of a Rat Model of Depression. Neuroscience 2013, 247, 191–200. [Google Scholar] [CrossRef]
  105. Liu, Y.; Yang, N.; Hao, W.; Zhao, Q.; Ying, T.; Liu, S.; Li, Q.; Liang, Y.; Wang, T.; Dong, Y.; et al. Dynamic Proteomic Analysis of Protein Expression Profiles in Whole Brain of Balb/c Mice Subjected to Unpredictable Chronic Mild Stress: Implications for Depressive Disorders and Future Therapies. Neurochem. Int. 2011, 58, 904–913. [Google Scholar] [CrossRef] [PubMed]
  106. Liu, W.; Zhou, C. Corticosterone Reduces Brain Mitochondrial Function and Expression of Mitofusin, BDNF in Depression-like Rodents Regardless of Exercise Preconditioning. Psychoneuroendocrinology 2012, 37, 1057–1070. [Google Scholar] [CrossRef]
  107. Carboni, L.; Piubelli, C.; Pozzato, C.; Astner, H.; Arban, R.; Righetti, P.G.; Hamdan, M.; Domenici, E. Proteomic Analysis of Rat Hippocampus after Repeated Psychosocial Stress. Neuroscience 2006, 137, 1237–1246. [Google Scholar] [CrossRef] [PubMed]
  108. Mallei, A.; Giambelli, R.; Gass, P.; Racagni, G.; Mathé, A.A.; Vollmayr, B.; Popoli, M. Synaptoproteomics of Learned Helpless Rats Involve Energy Metabolism and Cellular Remodeling Pathways in Depressive-like Behavior and Antidepressant Response. Neuropharmacology 2011, 60, 1243–1253. [Google Scholar] [CrossRef]
  109. Vollmayr, B.; Henn, F.A. Learned Helplessness in the Rat: Improvements in Validity and Reliability. Brain Res. Brain Res. Protoc. 2001, 8, 1–7. [Google Scholar] [CrossRef] [PubMed]
  110. Katz, R.J.; Roth, K.A.; Carroll, B.J. Acute and Chronic Stress Effects on Open Field Activity in the Rat: Implications for a Model of Depression. Neurosci. Biobehav. Rev. 1981, 5, 247–251. [Google Scholar] [CrossRef] [PubMed]
  111. Porsolt, R.D.; Bertin, A.; Jalfre, M. Behavioral Despair in Mice: A Primary Screening Test for Antidepressants. Arch. Int. Pharmacodyn. Ther. 1977, 229, 327–336. [Google Scholar]
  112. Landgraf, D.; Long, J.; Der-Avakian, A.; Streets, M.; Welsh, D.K. Dissociation of Learned Helplessness and Fear Conditioning in Mice: A Mouse Model of Depression. PLoS ONE 2015, 10, e0125892. [Google Scholar] [CrossRef] [PubMed]
  113. Sánchez, M.M.; Ladd, C.O.; Plotsky, P.M. Early Adverse Experience as a Developmental Risk Factor for Later Psychopathology: Evidence from Rodent and Primate Models. Dev. Psychopathol. 2001, 13, 419–449. [Google Scholar] [CrossRef]
  114. Becker, M.; Pinhasov, A.; Ornoy, A. Animal Models of Depression: What Can They Teach Us about the Human Disease? Diagnostics 2021, 11, 123. [Google Scholar] [CrossRef]
  115. Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The Tail Suspension Test: A New Method for Screening Antidepressants in Mice. Psychopharmacology 1985, 85, 367–370. [Google Scholar] [CrossRef] [PubMed]
  116. Nestler, E.J.; Gould, E.; Manji, H.; Buncan, M.; Duman, R.S.; Greshenfeld, H.K.; Hen, R.; Koester, S.; Lederhendler, I.; Meaney, M.; et al. Preclinical Models: Status of Basic Research in Depression. Biol. Psychiatry 2002, 52, 503–528. [Google Scholar] [CrossRef] [PubMed]
  117. Calvo, S.E.; Clauser, K.R.; Mootha, V.K. MitoCarta2.0: An Updated Inventory of Mammalian Mitochondrial Proteins. Nucleic Acids Res. 2016, 44, D1251–D1257. [Google Scholar] [CrossRef]
  118. Pei, L.; Wallace, D.C. Mitochondrial Etiology of Neuropsychiatric Disorders. Biol. Psychiatry 2018, 83, 722–730. [Google Scholar] [CrossRef] [PubMed]
  119. Martín-Jiménez, R.; Lurette, O.; Hebert-Chatelain, E. Damage in Mitochondrial DNA Associated with Parkinson’s Disease. DNA Cell Biol. 2020, 39, 1421–1430. [Google Scholar] [CrossRef]
  120. Fattal, O.; Link, J.; Quinn, K.; Cohen, B.H.; Franco, K. Psychiatric Comorbidity in 36 Adults with Mitochondrial Cytopathies. CNS Spectr. 2007, 12, 429–438. [Google Scholar] [CrossRef]
  121. Gardner, A.; Johansson, A.; Wibom, R.; Nennesmo, I.; von Döbeln, U.; Hagenfeldt, L.; Hällström, T. Alterations of Mitochondrial Function and Correlations with Personality Traits in Selected Major Depressive Disorder Patients. J. Affect. Disord. 2003, 76, 55–68. [Google Scholar] [CrossRef] [PubMed]
  122. Chang, C.-C.; Jou, S.-H.; Lin, T.-T.; Lai, T.-J.; Liu, C.-S. Mitochondria DNA Change and Oxidative Damage in Clinically Stable Patients with Major Depressive Disorder. PLoS ONE 2015, 10, e0125855. [Google Scholar] [CrossRef] [PubMed]
  123. Brymer, K.J.; Fenton, E.Y.; Kalynchuk, L.E.; Caruncho, H.J. Peripheral Etanercept Administration Normalizes Behavior, Hippocampal Neurogenesis, and Hippocampal Reelin and GABAA Receptor Expression in a Preclinical Model of Depression. Front. Pharmacol. 2018, 9, 121. [Google Scholar] [CrossRef]
  124. Wang, J.; Hodes, G.E.; Zhang, H.; Zhang, S.; Zhao, W.; Golden, S.A.; Bi, W.; Menard, C.; Kana, V.; Leboeuf, M.; et al. Epigenetic Modulation of Inflammation and Synaptic Plasticity Promotes Resilience against Stress in Mice. Nat. Commun. 2018, 9, 477. [Google Scholar] [CrossRef]
  125. Adzic, M.; Brkic, Z.; Bulajic, S.; Mitic, M.; Radojcic, M.B. Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders. Drug Dev. Res. 2016, 77, 400–406. [Google Scholar] [CrossRef] [PubMed]
  126. Inczedy-Farkas, G.; Trampush, J.W.; Perczel Forintos, D.; Beech, D.; Andrejkovics, M.; Varga, Z.; Remenyi, V.; Bereznai, B.; Gal, A.; Molnar, M.J. Mitochondrial DNA Mutations and Cognition: A Case-Series Report. Arch. Clin. Neuropsychol. 2014, 29, 315–321. [Google Scholar] [CrossRef]
  127. Munkholm, K.; Peijs, L.; Vinberg, M.; Kessing, L.V. A Composite Peripheral Blood Gene Expression Measure as a Potential Diagnostic Biomarker in Bipolar Disorder. Transl. Psychiatry 2015, 5, e614. [Google Scholar] [CrossRef]
  128. Ceylan, D.; Tuna, G.; Kirkali, G.; Tunca, Z.; Can, G.; Arat, H.E.; Kant, M.; Dizdaroglu, M.; Özerdem, A. Oxidatively-Induced DNA Damage and Base Excision Repair in Euthymic Patients with Bipolar Disorder. DNA Repair 2018, 65, 64–72. [Google Scholar] [CrossRef]
  129. Wang, Q.; Dwivedi, Y. Transcriptional Profiling of Mitochondria Associated Genes in Prefrontal Cortex of Subjects with Major Depressive Disorder. World J. Biol. Psychiatry 2017, 18, 592–603. [Google Scholar] [CrossRef]
  130. Shyn, S.I.; Shi, J.; Kraft, J.B.; Potash, J.B.; Knowles, J.A.; Weissman, M.M.; Garriock, H.A.; Yokoyama, J.S.; McGrath, P.J.; Peters, E.J.; et al. Novel Loci for Major Depression Identified by Genome-Wide Association Study of Sequenced Treatment Alternatives to Relieve Depression and Meta-Analysis of Three Studies. Mol. Psychiatry 2011, 16, 202–215. [Google Scholar] [CrossRef]
  131. El-Hattab, A.W.; Suleiman, J.; Almannai, M.; Scaglia, F. Mitochondrial Dynamics: Biological Roles, Molecular Machinery, and Related Diseases. Mol. Genet. Metab. 2018, 125, 315–321. [Google Scholar] [CrossRef] [PubMed]
  132. Scifo, E.; Pabba, M.; Kapadia, F.; Ma, T.; Lewis, D.A.; Tseng, G.C.; Sibille, E. Sustained Molecular Pathology Across Episodes and Remission in Major Depressive Disorder. Biol. Psychiatry 2018, 83, 81–89. [Google Scholar] [CrossRef] [PubMed]
  133. Villa, R.F.; Ferrari, F.; Bagini, L.; Gorini, A.; Brunello, N.; Tascedda, F. Mitochondrial Energy Metabolism of Rat Hippocampus after Treatment with the Antidepressants Desipramine and Fluoxetine. Neuropharmacology 2017, 121, 30–38. [Google Scholar] [CrossRef] [PubMed]
  134. Saia-Cereda, V.M.; Cassoli, J.S.; Martins-de-Souza, D.; Nascimento, J.M. Psychiatric Disorders Biochemical Pathways Unraveled by Human Brain Proteomics. Eur. Arch. Psychiatry Clin. Neurosci. 2017, 267, 3–17. [Google Scholar] [CrossRef] [PubMed]
  135. Zubenko, G.S.; Hughes III, H.B.; Jordan, R.M.; Lyons-Weiler, J.; Cohen, B.M. Differential Hippocampal Gene Expression and Pathway Analysis in an Etiology-Based Mouse Model of Major Depressive Disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014, 165, 457–466. [Google Scholar] [CrossRef] [PubMed]
  136. Carboni, L. The Contribution of Proteomic Studies in Humans, Animal Models, and after Antidepressant Treatments to Investigate the Molecular Neurobiology of Major Depression. PROTEOMICS–Clin. Appl. 2015, 9, 889–898. [Google Scholar] [CrossRef] [PubMed]
  137. Beasley, C.L.; Pennington, K.; Behan, A.; Wait, R.; Dunn, M.J.; Cotter, D. Proteomic Analysis of the Anterior Cingulate Cortex in the Major Psychiatric Disorders: Evidence for Disease-Associated Changes. PROTEOMICS 2006, 6, 3414–3425. [Google Scholar] [CrossRef]
  138. Martins-de-Souza, D. Proteomics, Metabolomics, and Protein Interactomics in the Characterization of the Molecular Features of Major Depressive Disorder. Dialogues Clin. Neurosci. 2014, 16, 63–73. [Google Scholar] [CrossRef]
  139. Karry, R.; Klein, E.; Ben Shachar, D. Mitochondrial Complex i Subunits Expression Is Altered in Schizophrenia: A Postmortem Study. Biol. Psychiatry 2004, 55, 676–684. [Google Scholar] [CrossRef]
  140. Martins-de-Souza, D.; Guest, P.C.; Vanattou-Saifoudine, N.; Rahmoune, H.; Bahn, S. Phosphoproteomic Differences in Major Depressive Disorder Postmortem Brains Indicate Effects on Synaptic Function. Eur. Arch. Psychiatry Clin. Neurosci. 2012, 262, 657–666. [Google Scholar] [CrossRef] [PubMed]
  141. Rappeneau, V.; Wilmes, L.; Touma, C. Molecular Correlates of Mitochondrial Dysfunctions in Major Depression: Evidence from Clinical and Rodent Studies. Mol. Cell. Neurosci. 2020, 109, 103555. [Google Scholar] [CrossRef] [PubMed]
  142. Johnston-Wilson, N.L.; Sims, C.D.; Hofmann, J.-P.; Anderson, L.; Shore, A.D.; Torrey, E.F.; Yolken, R.H. Disease-Specific Alterations in Frontal Cortex Brain Proteins in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder. Mol. Psychiatry 2000, 5, 142–149. [Google Scholar] [CrossRef]
  143. Taylor, M.J.; Freemantle, N.; Geddes, J.R.; Bhagwagar, Z. Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action: Systematic Review and Meta-Analysis. Arch. Gen. Psychiatry 2006, 63, 1217–1223. [Google Scholar] [CrossRef]
  144. Filipović, D.; Costina, V.; Perić, I.; Stanisavljević, A.; Findeisen, P. Chronic Fluoxetine Treatment Directs Energy Metabolism towards the Citric Acid Cycle and Oxidative Phosphorylation in Rat Hippocampal Nonsynaptic Mitochondria. Brain Res. 2017, 1659, 41–54. [Google Scholar] [CrossRef]
  145. Moretti, A.; Gorini, A.; Villa, R.F. Affective Disorders, Antidepressant Drugs and Brain Metabolism. Mol. Psychiatry 2003, 8, 773–785. [Google Scholar] [CrossRef]
  146. Sherman, A.D.; Sacquitne, J.L.; Petty, F. Specificity of the Learned Helplessness Model of Depression. Pharmacol. Biochem. Behav. 1982, 16, 449–454. [Google Scholar] [CrossRef]
  147. Kondo, D.G.; Hellem, T.L.; Sung, Y.-H.; Kim, N.; Jeong, E.-K.; DelMastro, K.K.; Shi, X.; Renshaw, P.F. Review: Magnetic Resonance Spectroscopy Studies of Pediatric Major Depressive Disorder. Depress. Res. Treat. 2011, 2011, 650450. [Google Scholar] [CrossRef]
  148. Ahmad, A.; Rasheed, N.; Banu, N.; Palit, G. Alterations in Monoamine Levels and Oxidative Systems in Frontal Cortex, Striatum, and Hippocampus of the Rat Brain during Chronic Unpredictable Stress. Stress Amst. Neth. 2010, 13, 355–364. [Google Scholar] [CrossRef]
  149. Tobe, E.H. Mitochondrial Dysfunction, Oxidative Stress, and Major Depressive Disorder. Neuropsychiatr. Dis. Treat. 2013, 9, 567–573. [Google Scholar] [CrossRef]
  150. Wen, L.; Jin, Y.; Li, L.; Sun, S.; Cheng, S.; Zhang, S.; Zhang, Y.; Svenningsson, P. Exercise Prevents Raphe Nucleus Mitochondrial Overactivity in a Rat Depression Model. Physiol. Behav. 2014, 132, 57–65. [Google Scholar] [CrossRef]
  151. Nathan, C.; Cunningham-Bussel, A. Beyond Oxidative Stress: An Immunologist’s Guide to Reactive Oxygen Species. Nat. Rev. Immunol. 2013, 13, 349–361. [Google Scholar] [CrossRef]
  152. Smith, R.A.J.; Hartley, R.C.; Cochemé, H.M.; Murphy, M.P. Mitochondrial Pharmacology. Trends Pharmacol. Sci. 2012, 33, 341–352. [Google Scholar] [CrossRef]
  153. He, L.; He, T.; Farrar, S.; Ji, L.; Liu, T.; Ma, X. Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species. Cell. Physiol. Biochem. 2017, 44, 532–553. [Google Scholar] [CrossRef]
  154. Czarny, P.; Kwiatkowski, D.; Kacperska, D.; Kawczyńska, D.; Talarowska, M.; Orzechowska, A.; Bielecka-Kowalska, A.; Szemraj, J.; Gałecki, P.; Śliwiński, T. Elevated Level of DNA Damage and Impaired Repair of Oxidative DNA Damage in Patients with Recurrent Depressive Disorder. Med. Sci. Monit. 2015, 21, 412–418. [Google Scholar] [CrossRef]
  155. Ullah, R.; Khan, M.; Shah, S.A.; Saeed, K.; Kim, M.O. Natural Antioxidant Anthocyanins—A Hidden Therapeutic Candidate in Metabolic Disorders with Major Focus in Neurodegeneration. Nutrients 2019, 11, 1195. [Google Scholar] [CrossRef]
  156. Palta, P.; Samuel, L.J.; Miller, E.R.; Szanton, S.L. Depression and Oxidative Stress: Results from a Meta-Analysis of Observational Studies. Psychosom. Med. 2014, 76, 12–19. [Google Scholar] [CrossRef]
  157. Black, C.N.; Bot, M.; Scheffer, P.G.; Cuijpers, P.; Penninx, B.W.J.H. Is Depression Associated with Increased Oxidative Stress? A Systematic Review and Meta-Analysis. Psychoneuroendocrinology 2015, 51, 164–175. [Google Scholar] [CrossRef]
  158. Ben-Shachar, D.; Karry, R. Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression. PLoS ONE 2008, 3, e3676. [Google Scholar] [CrossRef]
  159. Talarowska, M.; Orzechowska, A.; Szemraj, J.; Su, K.-P.; Maes, M.; Gałecki, P. Manganese Superoxide Dismutase Gene Expression and Cognitive Functions in Recurrent Depressive Disorder. Neuropsychobiology 2014, 70, 23–28. [Google Scholar] [CrossRef]
  160. Anderson, G. Linking the Biological Underpinnings of Depression: Role of Mitochondria Interactions with Melatonin, Inflammation, Sirtuins, Tryptophan Catabolites, DNA Repair and Oxidative and Nitrosative Stress, with Consequences for Classification and Cognition. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 80, 255–266. [Google Scholar] [CrossRef]
  161. Madrigal, J.L.; Olivenza, R.; Moro, M.A.; Lizasoain, I.; Lorenzo, P.; Rodrigo, J.; Leza, J.C. Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat Brain. Neuropsychopharmacology 2001, 24, 420–429. [Google Scholar] [CrossRef]
  162. Almeida, R.F.D.; Ganzella, M.; Machado, D.G.; Loureiro, S.O.; Leffa, D.; Quincozes-Santos, A.; Pettenuzzo, L.F.; Duarte, M.M.M.F.; Duarte, T.; Souza, D.O. Olfactory Bulbectomy in Mice Triggers Transient and Long-Lasting Behavioral Impairments and Biochemical Hippocampal Disturbances. Prog. Neuropsychopharmacol. Biol. Psychiatry 2017, 76, 1–11. [Google Scholar] [CrossRef]
  163. Holzmann, I.; da Silva, L.M.; Corrêa da Silva, J.A.; Steimbach, V.M.B.; de Souza, M.M. Antidepressant-like Effect of Quercetin in Bulbectomized Mice and Involvement of the Antioxidant Defenses, and the Glutamatergic and Oxidonitrergic Pathways. Pharmacol. Biochem. Behav. 2015, 136, 55–63. [Google Scholar] [CrossRef]
  164. Filiou, M.D.; Zhang, Y.; Teplytska, L.; Reckow, S.; Gormanns, P.; Maccarrone, G.; Frank, E.; Kessler, M.S.; Hambsch, B.; Nussbaumer, M.; et al. Proteomics and Metabolomics Analysis of a Trait Anxiety Mouse Model Reveals Divergent Mitochondrial Pathways. Biol. Psychiatry 2011, 70, 1074–1082. [Google Scholar] [CrossRef]
  165. Cooke, M.S.; Evans, M.D.; Dizdaroglu, M.; Lunec, J. Oxidative DNA Damage: Mechanisms, Mutation, and Disease. FASEB J. 2003, 17, 1195–1214. [Google Scholar] [CrossRef]
  166. Rizzuto, R.; De Stefani, D.; Raffaello, A.; Mammucari, C. Mitochondria as Sensors and Regulators of Calcium Signalling. Nat. Rev. Mol. Cell Biol. 2012, 13, 566–578. [Google Scholar] [CrossRef] [PubMed]
  167. Bravo-Sagua, R.; Parra, V.; López-Crisosto, C.; Díaz, P.; Quest, A.F.G.; Lavandero, S. Calcium Transport and Signaling in Mitochondria. In Comprehensive Physiology; John Wiley & Sons, Ltd: New York, NY, USA, 2017; pp. 623–634. ISBN 978-0-470-65071-4. [Google Scholar]
  168. Görlach, A.; Bertram, K.; Hudecova, S.; Krizanova, O. Calcium and ROS: A Mutual Interplay. Redox Biol. 2015, 6, 260–271. [Google Scholar] [CrossRef]
  169. Giorgi, C.; Marchi, S.; Pinton, P. The Machineries, Regulation and Cellular Functions of Mitochondrial Calcium. Nat. Rev. Mol. Cell Biol. 2018, 19, 713–730. [Google Scholar] [CrossRef]
  170. Belosludtsev, K.N.; Dubinin, M.V.; Belosludtseva, N.V.; Mironova, G.D. Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochem. Mosc. 2019, 84, 593–607. [Google Scholar] [CrossRef]
  171. Vollmayr, B.; Bachteler, D.; Vengeliene, V.; Gass, P.; Spanagel, R.; Henn, F. Rats with Congenital Learned Helplessness Respond Less to Sucrose but Show No Deficits in Activity or Learning. Behav. Brain Res. 2004, 150, 217–221. [Google Scholar] [CrossRef]
  172. Rygula, R.; Abumaria, N.; Flügge, G.; Fuchs, E.; Rüther, E.; Havemann-Reinecke, U. Anhedonia and Motivational Deficits in Rats: Impact of Chronic Social Stress. Behav. Brain Res. 2005, 162, 127–134. [Google Scholar] [CrossRef]
  173. Kabir, Z.D.; Lee, A.S.; Burgdorf, C.E.; Fischer, D.K.; Rajadhyaksha, A.M.; Mok, E.; Rizzo, B.; Rice, R.C.; Singh, K.; Ota, K.T.; et al. Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1. Neuropsychopharmacology 2017, 42, 2032–2042. [Google Scholar] [CrossRef]
  174. Ebert, D.H.; Greenberg, M.E. Activity-Dependent Neuronal Signalling and Autism Spectrum Disorder. Nature 2013, 493, 327–337. [Google Scholar] [CrossRef]
  175. Bhat, S.; Dao, D.T.; Terrillion, C.E.; Arad, M.; Smith, R.J.; Soldatov, N.M.; Gould, T.D. CACNA1C (Cav1.2) in the Pathophysiology of Psychiatric Disease. Prog. Neurobiol. 2012, 99, 1–14. [Google Scholar] [CrossRef]
  176. Kabir, Z.D.; Lee, A.S.; Rajadhyaksha, A.M. L-Type Ca2+ Channels in Mood, Cognition and Addiction: Integrating Human and Rodent Studies with a Focus on Behavioural Endophenotypes. J. Physiol. 2016, 594, 5823–5837. [Google Scholar] [CrossRef]
  177. Dao, D.T.; Mahon, P.B.; Cai, X.; Kovacsics, C.E.; Blackwell, R.A.; Arad, M.; Shi, J.; Zandi, P.P.; O’Donnell, P.; Knowles, J.A.; et al. Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans. Biol. Psychiatry 2010, 68, 801–810. [Google Scholar] [CrossRef]
  178. Cross-Disorder Group of the Psychiatric Genomics Consortium Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-Wide Analysis. Lancet Lond. Engl. 2013, 381, 1371–1379. [CrossRef]
  179. Dedic, N.; Pöhlmann, M.L.; Richter, J.S.; Mehta, D.; Czamara, D.; Metzger, M.W.; Dine, J.; Bedenk, B.T.; Hartmann, J.; Wagner, K.V.; et al. Cross-Disorder Risk Gene CACNA1C Differentially Modulates Susceptibility to Psychiatric Disorders during Development and Adulthood. Mol. Psychiatry 2018, 23, 533–543. [Google Scholar] [CrossRef]
  180. Michels, S.; Ganjam, G.K.; Martins, H.; Schratt, G.M.; Wöhr, M.; Schwarting, R.K.W.; Culmsee, C. Downregulation of the Psychiatric Susceptibility Gene Cacna1c Promotes Mitochondrial Resilience to Oxidative Stress in Neuronal Cells. Cell Death Discov. 2018, 4. [Google Scholar] [CrossRef]
  181. Pariante, C.M. Why Are Depressed Patients Inflamed? A Reflection on 20 Years of Research on Depression, Glucocorticoid Resistance and Inflammation. Eur. Neuropsychopharmacol. 2017, 27, 554–559. [Google Scholar] [CrossRef]
  182. Fries, G.R.; Saldana, V.A.; Finnstein, J.; Rein, T. Molecular Pathways of Major Depressive Disorder Converge on the Synapse. Mol. Psychiatry 2022, 1–14. [Google Scholar] [CrossRef]
  183. Steptoe, A.; Hamer, M.; Chida, Y. The Effects of Acute Psychological Stress on Circulating Inflammatory Factors in Humans: A Review and Meta-Analysis. Brain. Behav. Immun. 2007, 21, 901–912. [Google Scholar] [CrossRef]
  184. Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E.K.; Lanctôt, K.L. A Meta-Analysis of Cytokines in Major Depression. Biol. Psychiatry 2010, 67, 446–457. [Google Scholar] [CrossRef]
  185. Miller, A.H.; Maletic, V.; Raison, C.L. Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression. Biol. Psychiatry 2009, 65, 732–741. [Google Scholar] [CrossRef]
  186. Leonard, B.; Maes, M. Mechanistic Explanations How Cell-Mediated Immune Activation, Inflammation and Oxidative and Nitrosative Stress Pathways and Their Sequels and Concomitants Play a Role in the Pathophysiology of Unipolar Depression. Neurosci. Biobehav. Rev. 2012, 36, 764–785. [Google Scholar] [CrossRef]
  187. Song, C.; Halbreich, U.; Han, C.; Leonard, B.E.; Luo, H. Imbalance between Pro- and Anti-Inflammatory Cytokines, and between Th1 and Th2 Cytokines in Depressed Patients: The Effect of Electroacupuncture or Fluoxetine Treatment. Pharmacopsychiatry 2009, 42, 182–188. [Google Scholar] [CrossRef]
  188. Shizuya, K.; Komori, T.; Fujiwara, R.; Miyahara, S.; Ohmori, M.; Nomura, J. The Influence of Restraint Stress on the Expression of MRNAs for IL-6 and the IL-6 Receptor in the Hypothalamus and Midbrain of the Rat. Life Sci. 1997, 61, PL135–PL140. [Google Scholar] [CrossRef]
  189. Shintani, F.; Nakaki, T.; Kanba, S.; Sato, K.; Yagi, G.; Shiozawa, M.; Aiso, S.; Kato, R.; Asai, M. Involvement of Interleukin-1 in Immobilization Stress-Induced Increase in Plasma Adrenocorticotropic Hormone and in Release of Hypothalamic Monoamines in the Rat. J. Neurosci. Off. J. Soc. Neurosci. 1995, 15, 1961–1970. [Google Scholar] [CrossRef]
  190. Kaster, M.P.; Gadotti, V.M.; Calixto, J.B.; Santos, A.R.S.; Rodrigues, A.L.S. Depressive-like Behavior Induced by Tumor Necrosis Factor-α in Mice. Neuropharmacology 2012, 62, 419–426. [Google Scholar] [CrossRef]
  191. Valerio, A.; Cardile, A.; Cozzi, V.; Bracale, R.; Tedesco, L.; Pisconti, A.; Palomba, L.; Cantoni, O.; Clementi, E.; Moncada, S.; et al. TNF-Alpha Downregulates ENOS Expression and Mitochondrial Biogenesis in Fat and Muscle of Obese Rodents. J. Clin. Investig. 2006, 116, 2791–2798. [Google Scholar] [CrossRef]
  192. Najjar, S.; Pearlman, D.M.; Alper, K.; Najjar, A.; Devinsky, O. Neuroinflammation and Psychiatric Illness. J. Neuroinflamm. 2013, 10, 816. [Google Scholar] [CrossRef]
  193. Maes, M.; Ruckoanich, P.; Chang, Y.S.; Mahanonda, N.; Berk, M. Multiple Aberrations in Shared Inflammatory and Oxidative & Nitrosative Stress (IO&NS) Pathways Explain the Co-Association of Depression and Cardiovascular Disorder (CVD), and the Increased Risk for CVD and Due Mortality in Depressed Patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011, 35, 769–783. [Google Scholar] [CrossRef]
  194. Samavati, L.; Lee, I.; Mathes, I.; Lottspeich, F.; Hüttemann, M. Tumor Necrosis Factor α Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase. J. Biol. Chem. 2008, 283, 21134–21144. [Google Scholar] [CrossRef] [PubMed]
  195. Adzic, M.; Djordjevic, J.; Mitic, M.; Brkic, Z.; Lukic, I.; Radojcic, M. The Contribution of Hypothalamic Neuroendocrine, Neuroplastic and Neuroinflammatory Processes to Lipopolysaccharide-Induced Depressive-like Behaviour in Female and Male Rats: Involvement of Glucocorticoid Receptor and C/EBP-β. Behav. Brain Res. 2015, 291, 130–139. [Google Scholar] [CrossRef]
  196. Chen, W.-J.; Du, J.-K.; Hu, X.; Yu, Q.; Li, D.-X.; Wang, C.-N.; Zhu, X.-Y.; Liu, Y.-J. Protective Effects of Resveratrol on Mitochondrial Function in the Hippocampus Improves Inflammation-Induced Depressive-like Behavior. Physiol. Behav. 2017, 182, 54–61. [Google Scholar] [CrossRef] [PubMed]
  197. Brkic, Z.; Zivanovic, A.; Adzic, M. Sex-Specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression. Neuroscience 2020, 451, 174–183. [Google Scholar] [CrossRef]
  198. Haj-Mirzaian, A.; Amiri, S.; Amini-Khoei, H.; Hosseini, M.-J.; Haj-Mirzaian, A.; Momeny, M.; Rahimi-Balaei, M.; Dehpour, A.R. Anxiety- and Depressive-Like Behaviors Are Associated with Altered Hippocampal Energy and Inflammatory Status in a Mouse Model of Crohn’s Disease. Neuroscience 2017, 366, 124–137. [Google Scholar] [CrossRef] [PubMed]
Table 1. Animal models of depression show various signs of mitochondrial dysfunction.
Table 1. Animal models of depression show various signs of mitochondrial dysfunction.
Depression ProtocolDepression-like BehaviorMitochondrial AlterationRef.
Prenatal stressNot analyzedDifferent expression of TOM70 and ATP5F1C [91]
Maternal separationIncreased immobilization time in the forced swim testUpregulation of GLUD1, ATP5F1A and ATP5PD, and downregulation of IDH3A[92,93]
Reduced appetite, anhedoniaDownregulation of fumarate hydratase and IDH; upregulation of citrate synthase[94,95]
Not analyzedDownregulation of ATP5F1B, complex III subunit I, PDHE1-B[96]
Chronic mild stressAnhedoniaModified expression of Hsp60[97]
AnhedoniaUpregulation of ATP5F1C, IDH3B, complex I 75 kDa subunit[98]
AnhedoniaUpregulation of NDUFB7, COX5A, COX5B [99]
AnhedoniaDownregulation of MDH[100]
AnhedoniaUpregulation of COXVa, downregulation of IDH3A and ACO2[101]
Anhedonia, reduced weight and decreased locomotionDownregulation of OGDH, NDUFS3[102]
Anhedonia, no weight gainInhibition of Complex I, III and IV activities in cerebral cortex and cerebellum but not in hippocampus, prefrontal cortex and striatum[103]
Anhedonia, reduced body weight, increased immobility in the tail suspension testReduced O2 consumption, mitochondrial depolarization in hippocampus, cortex and hypothalamus[104]
Unpredictable chronic mild stressAnhedonia, increased immobilization time in the forced swim testUpregulation of NDUFA4, COXVIb-1, complex III subunit 1, MDH; downregulation of SDHA and SOD2[105]
Anhedonia, increased immobilization time in the forced swim testDownregulation of MFN1, MFN2 and DOD2; reduced activity of complex I and IV, mitochondrial depolarization[106]
Social defeat stressReduced locomotion in the open field testUpregulation of ACO1 and GDH; downregulation of MDH and GRP75 [107]
Learned helplessnessReduced active avoidanceDownregulation of ATP5F1A, fumarate hydratase, HSP70, PDHE1-B, EF-Tu, GDH, MDH and aconitase[108,109]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Khan, M.; Baussan, Y.; Hebert-Chatelain, E. Connecting Dots between Mitochondrial Dysfunction and Depression. Biomolecules 2023, 13, 695.

AMA Style

Khan M, Baussan Y, Hebert-Chatelain E. Connecting Dots between Mitochondrial Dysfunction and Depression. Biomolecules. 2023; 13(4):695.

Chicago/Turabian Style

Khan, Mehtab, Yann Baussan, and Etienne Hebert-Chatelain. 2023. "Connecting Dots between Mitochondrial Dysfunction and Depression" Biomolecules 13, no. 4: 695.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop