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Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!
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Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!

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 March 2023) | Viewed by 23051

Special Issue Editor

Dr. Sónia Catarina Correia

E-Mail Website
Guest Editor
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
Interests: Alzheimer’s disease; mitochondria; brain tolerance; hypoxia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Representing one of the leading causes of mortality globally, neurodegenerative disorders comprise a heterogeneous group of pathological conditions characterized by the progressive dysfunction and loss of selective neuronal populations. Although the “trigger(s)” of neurodegenerative disorders remains enigmatic, decades of research revealed that mitochondrial dysfunction represents a ubiquitous pathological feature being considered a "convergence point" for neurodegeneration.  This is not surprising since mitochondria are the primary source of energy in neurons. Mitochondrial dynamics are tightly orchestrated to meet the fluctuating and compartmentalized energy requirements of neurons. Importantly, recent scientific advances also posited mitochondria at the interface between neurodegeneration and neuroinflammation.

Within this scenario, the Special Issue “Mitochondria in neurodegenerative disorders: when the powerhouse fails” welcomes the submission of original research or review articles covering the current state-of-the-art on the involvement of different aspects of mitochondrial biology on the pathological course of neurodegenerative disorders and the potential of mitochondrial medicine.

Dr. Sónia Catarina Correia
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegenerative disorders
  • mitochondrial bioenergetics
  • mitochondrial fusion-fission
  • mitophagy
  • mitochondrial trafficking
  • neuroinflammation
  • biomarkers
  • mitochondrial medicine

Published Papers (7 papers)

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Research

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15 pages, 2444 KiB  
Article
Mitochondrial Effects of Hydromethylthionine, Rivastigmine and Memantine in Tau-Transgenic Mice
by Constantin Kondak, Michael Leith, Thomas C. Baddeley, Renato X. Santos, Charles R. Harrington, Claude M. Wischik, Gernot Riedel and Jochen Klein
Int. J. Mol. Sci. 2023, 24(13), 10810; https://doi.org/10.3390/ijms241310810 - 28 Jun 2023
Viewed by 1268
Abstract
Tau protein aggregations are important contributors to the etiology of Alzheimer’s disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the [...] Read more.
Tau protein aggregations are important contributors to the etiology of Alzheimer’s disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2–4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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18 pages, 3682 KiB  
Article
CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons
by Rocío García-Arroyo, Gemma Marfany and Serena Mirra
Int. J. Mol. Sci. 2022, 23(19), 11593; https://doi.org/10.3390/ijms231911593 - 30 Sep 2022
Cited by 2 | Viewed by 1623
Abstract
Mutations in the Ceramide Kinase-like (CERKL) gene cause retinal dystrophies, characterized by progressive degeneration of retinal neurons, which eventually lead to vision loss. Among other functions, CERKL is involved in the regulation of autophagy, mitochondrial dynamics, and metabolism in the retina. [...] Read more.
Mutations in the Ceramide Kinase-like (CERKL) gene cause retinal dystrophies, characterized by progressive degeneration of retinal neurons, which eventually lead to vision loss. Among other functions, CERKL is involved in the regulation of autophagy, mitochondrial dynamics, and metabolism in the retina. However, CERKL is nearly ubiquitously expressed, and it has been recently described to play a protective role against brain injury. Here we show that Cerkl is expressed in the hippocampus, and we use mouse hippocampal neurons to explore the impact of either overexpression or depletion of CERKL on mitochondrial trafficking and dynamics along axons. We describe that a pool of CERKL localizes at mitochondria in hippocampal axons. Importantly, the depletion of CERKL in the CerklKD/KO mouse model is associated with changes in the expression of fusion/fission molecular regulators, induces mitochondrial fragmentation, and impairs axonal mitochondrial trafficking. Our findings highlight the role of CERKL, a retinal dystrophy gene, in the regulation of mitochondrial health and homeostasis in central nervous system anatomic structures other than the retina. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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Review

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20 pages, 3182 KiB  
Review
Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases
by Germán Plascencia-Villa and George Perry
Int. J. Mol. Sci. 2023, 24(15), 12486; https://doi.org/10.3390/ijms241512486 - 06 Aug 2023
Cited by 3 | Viewed by 3463
Abstract
The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer’s [...] Read more.
The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer’s and Parkinson’s disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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19 pages, 1120 KiB  
Review
Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations
by Matteo Fields, Annalisa Marcuzzi, Arianna Gonelli, Claudio Celeghini, Natalia Maximova and Erika Rimondi
Int. J. Mol. Sci. 2023, 24(4), 3739; https://doi.org/10.3390/ijms24043739 - 13 Feb 2023
Cited by 14 | Viewed by 2735
Abstract
Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction [...] Read more.
Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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25 pages, 1461 KiB  
Review
mtUPR Modulation as a Therapeutic Target for Primary and Secondary Mitochondrial Diseases
by Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Suleva Povea-Cabello, Alejandra Suárez-Carrillo, Ana Romero-González, Juan Miguel Suárez-Rivero, Jose Manuel Romero-Domínguez and Jose Antonio Sánchez-Alcázar
Int. J. Mol. Sci. 2023, 24(2), 1482; https://doi.org/10.3390/ijms24021482 - 12 Jan 2023
Cited by 8 | Viewed by 4139
Abstract
Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and [...] Read more.
Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and secondary mitochondrial diseases to this day. Therefore, new therapeutic approaches, such as the modulation of the mitochondrial unfolded protein response (mtUPR), are being explored. mtUPRs englobe several compensatory processes related to proteostasis and antioxidant system mechanisms. mtUPR activation, through an overcompensation for mild intracellular stress, promotes cell homeostasis and improves lifespan and disease alterations in biological models of mitochondrial dysfunction in age-related diseases, cardiopathies, metabolic disorders, and primary mitochondrial diseases. Although mtUPR activation is a promising therapeutic option for many pathological conditions, its activation could promote tumor progression in cancer patients, and its overactivation could lead to non-desired side effects, such as the increased heteroplasmy of mitochondrial DNA mutations. In this review, we present the most recent data about mtUPR modulation as a therapeutic approach, its role in diseases, and its potential negative consequences in specific pathological situations. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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20 pages, 647 KiB  
Review
Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies
by Mariana Pires and Ana Cristina Rego
Int. J. Mol. Sci. 2023, 24(1), 778; https://doi.org/10.3390/ijms24010778 - 01 Jan 2023
Cited by 22 | Viewed by 5659
Abstract
APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, [...] Read more.
APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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42 pages, 4104 KiB  
Review
S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases
by Sofia Vrettou and Brunhilde Wirth
Int. J. Mol. Sci. 2022, 23(24), 15849; https://doi.org/10.3390/ijms232415849 - 13 Dec 2022
Cited by 15 | Viewed by 2934
Abstract
Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from [...] Read more.
Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia. Full article
(This article belongs to the Special Issue Mitochondria in Neurodegenerative Disorders: When the Powerhouse Fails!)
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