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Mitochondria as a Cellular Hub in Neurological Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 20162

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Dr. Anna Atlante

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Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM)-CNR, Via G. Amendola122/O, 70126 Bari, Italy
Interests: mitochondrial bioenergetics; oxidative phosphorylation; mitochondrial dysfunction; metabolic regulation; oxidative stress; apoptosis; Alzheimer’s disease; cystic fibrosis
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Dear Colleagues,

Research on mitochondrial function, an indicator of cell health, continues to be fervid.

Mitochondria receive great attention because they emerge as hubs on which cell survival or cell death is ultimately determined. Without ATP from the cell’s powerhouse, cell survival is endangered in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, epilepsy, stroke, and others. All of these diseases that significantly change the lives of millions of people are characterized by structural, biochemical, or electrical abnormalities in the brain, spinal cord, or other nerves, affecting memory and the ability to perform daily activities.

Morphologic, biochemical, and molecular genetic studies posit that mitochondria constitute a convergence point for these neurological disorders.

The aim of this Special Issue of the International Journal of Molecular Sciences “Mitochondria in Neurological Disorders” is to underline the advances and the most recent discoveries in all fields of science that deal with the role of mitochondria in neurological disorders.

Original full research articles, as well as review articles from research groups all over the world, are welcome in order to disseminate the scientific knowledge on this interesting topic.

Dr. Anna Atlante
Guest Editor

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Keywords

mitochondria
Bioenergetics
ROS production
Mitochondrial DNA
Neurodegeneration
Neurotoxicity
Apoptosis
Alzheimer’s disease
Parkinson’s disease
Huntington's disease
Multiple sclerosis
Epilepsy
Stroke

Related Special Issue

Mitochondria as a Cellular Hub in Neurological Disorders 2.0 in International Journal of Molecular Sciences (5 articles)

Published Papers (8 papers)

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Research

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21 pages, 2315 KiB

Open AccessArticle

Acute Ozone-Induced Transcriptional Changes in Markers of Oxidative Stress and Glucocorticoid Signaling in the Rat Hippocampus and Hypothalamus Are Sex-Specific

by Matthew C. Valdez, Danielle L. Freeborn, Padmaja Vulimiri, Joseph M. Valdez, Urmila P. Kodavanti and Prasada Rao S. Kodavanti

Int. J. Mol. Sci. 2023, 24(7), 6404; https://doi.org/10.3390/ijms24076404 - 29 Mar 2023

Viewed by 1434

Abstract

Exposure to a prototypic air pollutant ozone (O₃) has been associated with the activation of neuroendocrine stress response along with neural changes in oxidative stress (OS), inflammation, and Alzheimer’s disease-like pathologies in susceptible animal models. We hypothesized that neural oxidative and transcriptional changes induced by O₃ in stress responsive regions are sex-dependent. Male and female adult Long–Evans rats were exposed to filtered air or O₃ for two consecutive days (0.8 ppm, 4 h/day) and brain regions were flash-frozen. Activities of cerebellar OS parameters and mitochondrial complex I, II, and IV enzymes were assessed to confirm prior findings. We assessed transcriptional changes in hypothalamus (HYP) and hippocampus (HIP) for markers of OS, microglial activity and glucocorticoid signaling using qPCR. Although there were no O₃ or sex-related differences in the cerebellar activities of OS and mitochondrial enzymes, the levels of protein carbonyls and complex II activities were higher in females regardless of O₃. There were no statistical differences in baseline expression of genes related to OS (Cat, Dhcr24, Foxm1, Gpx1, Gss, Nfe2l2, Sod1) except for lower HYP Sod1 expression in air-exposed females than males, and higher HIP Gss expression in O₃-exposed females relative to matched males. Microglial marker Aif1 expression was higher in O₃-exposed females relative to males; O₃ inhibited Itgam only in males. The expression of Bdnf in HIP and HYP was inhibited by O₃ in both sexes. Genes related to glucocorticoid signaling (Fkbp4, Fkbp5, Hsp90aa1, Hspa4, nr3c1, nr3c2) showed sex-specific effects due to O₃ exposure. Baseline expression of HIP Fkbp4 was higher in females relative to males. O₃ inhibited Nr3c1 in female HIP and male HYP, but Nr3c2 was inhibited in male HYP. Fkbp4 expression was higher in O₃-exposed females when compared to matched males, whereas Fkbp5 was expressed at higher levels in both brain regions of males and females. These results indicate that sex-specific brain region responses to O₃ might, in part, be caused by OS and regulation of glucocorticoid signaling. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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21 pages, 2370 KiB

Open AccessArticle

by Artem P. Gureev, Victoria G. Khorolskaya, Irina S. Sadovnikova, Ekaterina A. Shaforostova, Vadim R. Cherednichenko, Inna Y. Burakova, Egor Y. Plotnikov and Vasily N. Popov

Int. J. Mol. Sci. 2022, 23(23), 15197; https://doi.org/10.3390/ijms232315197 - 02 Dec 2022

Cited by 8 | Viewed by 1676

Abstract

In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in Bdnf expression in the hippocampus, Nfe2l2 expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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14 pages, 1590 KiB

Open AccessArticle

Redox Active α-Lipoic Acid Differentially Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer and Its Control Cells

by Fabian Dieter, Carsten Esselun and Gunter P. Eckert

Int. J. Mol. Sci. 2022, 23(16), 9186; https://doi.org/10.3390/ijms23169186 - 16 Aug 2022

Cited by 8 | Viewed by 2024

Abstract

Introduction: Alpha lipoic acid (ALA) is a sulphur-containing organic compound, derived from octanoic acid, and an important cofactor for mitochondrial respiratory enzymes. It has strong antioxidant properties that improve mitochondrial function. We investigated if ALA improves mitochondrial dysfunction in a cellular model of Alzheimer’s disease (AD). Methods: SH-SY5Y-APP₆₉₅ cells were used as a model for an early stage of AD. Vector-transfected SH-SY5Y-MOCK cells served as controls. Using these cells, we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, and citrate synthase activity (CS) in cells treated with ALA. Cells were treated for 24 h with different concentrations of ALA and with or without the complex I inhibitor rotenone. Results: Incubation with ALA showed a significant increase in ATP levels in both SH-SY5Y-APP₆₉₅ and SH-SY5Y-MOCK cells. MMP levels were elevated in SH-SY5Y-MOCK cells, treatment with rotenone showed a reduction in MMP, which could be partly alleviated after incubation with ALA in SH-SY5Y-MOCK cells. ALA treatment showed significant differences in respiration chain complex activities in SH-SY5Y-MOCK cells. Citrate synthase activity was unaffected. ROS levels were significantly lower in both cell lines treated with ALA. Conclusions: ALA increased the activity of the different complexes of the respiratory chain, and consequently enhanced the MMP, leading to increased ATP levels indicating improved mitochondrial function. ALA only marginally protects from additional rotenone-induced mitochondrial stress. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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21 pages, 3016 KiB

Open AccessArticle

Effects of Combining Biofactors on Bioenergetic Parameters, Aβ Levels and Survival in Alzheimer Model Organisms

by Lukas Babylon, Fabian Schmitt, Yannik Franke, Tim Hubert and Gunter P. Eckert

Int. J. Mol. Sci. 2022, 23(15), 8670; https://doi.org/10.3390/ijms23158670 - 04 Aug 2022

Cited by 5 | Viewed by 1972

Abstract

Increased amyloid beta (Aβ) levels and mitochondrial dysfunction (MD) in the human brain characterize Alzheimer disease (AD). Folic acid, magnesium and vitamin B6 are essential micro-nutrients that may provide neuroprotection. Bioenergetic parameters and amyloid precursor protein (APP) processing products were investigated in vitro in human neuroblastoma SH-SY5Y-APP695 cells, expressing neuronal APP, and in vivo, in the invertebrate Caenorhabditis elegans (CL2006 & GMC101) expressing muscular APP. Model organisms were incubated with either folic acid and magnesium-orotate (ID63) or folic acid, magnesium-orotate and vitamin B6 (ID64) in different concentrations. ID63 and ID64 reduced Aβ, soluble alpha APP (sAPPα), and lactate levels in SH-SY5Y-APP695 cells. The latter might be explained by enhanced expression of lactate dehydrogenase (LDHA). Micronutrient combinations had no effects on mitochondrial parameters in SH-SY5Y-APP695 cells. ID64 showed a significant life-prolonging effect in C. elegans CL2006. Incubation of GMC101 with ID63 significantly lowered Aβ aggregation. Both combinations significantly reduced paralysis and thus improved the phenotype in GMC101. Thus, the combinations of the tested biofactors are effective in pre-clinical models of AD by interfering with Aβ related pathways and glycolysis. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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Review

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14 pages, 1235 KiB

Open AccessReview

Simple to Complex: The Role of Actin and Microtubules in Mitochondrial Dynamics in Amoeba, Yeast, and Mammalian Cells

by Meghan D. Jones and Kari Naylor

Int. J. Mol. Sci. 2022, 23(16), 9402; https://doi.org/10.3390/ijms23169402 - 20 Aug 2022

Cited by 3 | Viewed by 2503

Abstract

Mitochondria are complex organelles that provide energy for the cell in the form of adenosine triphosphate (ATP) and have very specific structures. For most organisms, this is a reticular or tubular mitochondrial network, while others have singular oval-shaped organelles. Nonetheless, maintenance of this structure is dependent on the mitochondrial dynamics, fission, fusion, and motility. Recently, studies have shown that the cytoskeleton has a significant role in the regulation of mitochondrial dynamics. In this review, we focus on microtubules and actin filaments and look at what is currently known about the cytoskeleton’s role in mitochondrial dynamics in complex models like mammals and yeast, as well as what is known in the simple model system, Dictyostelium discoideum. Understanding how the cytoskeleton is involved in mitochondrial dynamics increases our understanding of mitochondrial disease, especially neurodegenerative diseases. Increases in fission, loss of fusion, and fragmented mitochondria are seen in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s disease. There is no known cure for these diseases, but new therapeutic strategies using drugs to alter mitochondrial fusion and fission activity are being considered. The future of these therapeutic studies is dependent on an in-depth understanding of the mechanisms of mitochondrial dynamics. Understanding the cytoskeleton’s role in dynamics in multiple model organisms will further our understanding of these mechanisms and could potentially uncover new therapeutic targets for these neurodegenerative diseases. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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21 pages, 1259 KiB

Open AccessReview

Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells

by Anna Atlante, Daniela Valenti, Valentina Latina and Giuseppina Amadoro

Int. J. Mol. Sci. 2022, 23(14), 7722; https://doi.org/10.3390/ijms23147722 - 13 Jul 2022

Cited by 16 | Viewed by 2317

Abstract

Alzheimer’s disease (AD), certainly the most widespread proteinopathy, has as classical neuropathological hallmarks, two groups of protein aggregates: senile plaques and neurofibrillary tangles. However, the research interest is rapidly gaining ground in a better understanding of other pathological features, first, of all the mitochondrial dysfunctions. Several pieces of evidence support the hypothesis that abnormal mitochondrial function may trigger aberrant processing of amyloid progenitor protein or tau and thus neurodegeneration. Here, our aim is to emphasize the role played by two ‘bioenergetic’ proteins inserted in the mitochondrial membranes, inner and outer, respectively, that is, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), in the progression of AD. To perform this, we will magnify the ANT and VDAC defects, which are measurable hallmarks of mitochondrial dysfunction, and collect all the existing information on their interaction with toxic Alzheimer’s proteins. The pathological convergence of tau and amyloid β-peptide (Aβ) on mitochondria may finally explain why the therapeutic strategies used against the toxic forms of Aβ or tau have not given promising results separately. Furthermore, the crucial role of ANT-1 and VDAC impairment in the onset/progression of AD opens a window for new therapeutic strategies aimed at preserving/improving mitochondrial function, which is suspected to be the driving force leading to plaque and tangle deposition in AD. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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16 pages, 1825 KiB

Open AccessReview

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

by Ashly Hindle, Sharda P. Singh, Jangampalli Adi Pradeepkiran, Chhanda Bose, Murali Vijayan, Sudhir Kshirsagar, Neha A. Sawant and P. Hemachandra Reddy

Int. J. Mol. Sci. 2022, 23(11), 6098; https://doi.org/10.3390/ijms23116098 - 29 May 2022

Cited by 10 | Viewed by 3413

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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35 pages, 142194 KiB

Open AccessReview

The Mighty Mitochondria Are Unifying Organelles and Metabolic Hubs in Multiple Organs of Obesity, Insulin Resistance, Metabolic Syndrome, and Type 2 Diabetes: An Observational Ultrastructure Study

by Melvin R. Hayden

Int. J. Mol. Sci. 2022, 23(9), 4820; https://doi.org/10.3390/ijms23094820 - 27 Apr 2022

Cited by 14 | Viewed by 3584

Abstract

Mitochondria (Mt) are essential cellular organelles for the production of energy and thermogenesis. Mt also serve a host of functions in addition to energy production, which include cell signaling, metabolism, cell death, and aging. Due to the central role of Mt in metabolism as metabolic hubs, there has been renewed interest in how Mt impact metabolic pathways and multiple pathologies. This review shares multiple observational ultrastructural findings in multiple cells and organs to depict aberrant mitochondrial (aMt) remodeling in pre-clinical rodent models. Further, it is intended to show how remodeling of Mt are associated with obesity, insulin resistance, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). Specifically, Mt remodeling in hypertensive and insulin-resistant lean models (Ren2 rat models), lean mice with streptozotocin-induced diabetes, obesity models including diet-induced obesity, genetic leptin-deficient ob/ob, and leptin receptor-deficient db/db diabetic mice are examined. Indeed, aMt dysfunction and damage have been implicated in multiple pathogenic diseases. Manipulation of Mt such as the induction of Mt biogenesis coupled with improvement of mitophagy machinery may be helpful to remove leaky damaged aMt in order to prevent the complications associated with the generation of superoxide-derived reactive oxygen species and the subsequent reactive species interactome. A better understanding of Mt remodeling may help to unlock many of the mysteries in obesity, insulin resistance, MetS, T2DM, and the associated complications of diabetic end-organ disease. Full article

(This article belongs to the Special Issue Mitochondria as a Cellular Hub in Neurological Disorders)

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