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Mitochondrial Dysfunction in Neurodegenerative Diseases

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: 10 June 2024 | Viewed by 11716

Special Issue Editors

Independent Researcher, New York, NY 10021, USA
Interests: neurological diseases; pathophysiology; therapeutics; animal models; molecular mechanisms; drug development; mitochondria; biomarker; posttranslational modification; transcription factor; gut-brain axis; Huntington’s disease; Parkinson’s disease; Alzheimer’s disease
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Guest Editor
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA
Interests: neurodegeneration; brain; mitochondria; posttranslational modification; animal models; evolution

Special Issue Information

Dear Colleagues,

Mitochondria, as the tiny cellular organelles that serve as both guardians as well as the executioners of a variety of cellular functions essential for cell survival, have rightly claimed their place in the forefront of investigations relating to neurodegeneration. Alterations in mitochondrial bioenergetics, dynamics (fission–fusion, movement), mitophagy and oxidative stress originating at mitochondria have long been intertwined as causative factors for neurodegenerative diseases. Neurodegeneration itself is a very complex process, and the various factors involved in its aetiology are not yet fully understood, which is why there are no disease-modifying therapies available. However, the future is not bleak; with recent technological advances, it is now possible to probe further than ever before into the mitochondria-related mechanisms of neurodegeneration. New factors, interactions and processes are being discovered every day. We are poised to make great strides towards finding a cure and, with our Special Issue, we hope to take advantage of this crucial turning point. We intend to provoke a healthy and fruitful discussion on mitochondria-targeted therapies in development and bring to the fore new and current advances in the understanding and clinical development of some of these disease mechanisms, biomarkers and therapies. 

Dr. Ashu Johri
Dr. Abhishek Chandra
Guest Editors

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Keywords

  • neurodegeneration
  • mitochondria
  • biomarker
  • therapeutics
  • clinical development

Published Papers (5 papers)

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Research

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15 pages, 4259 KiB  
Article
Dopamine Release Neuroenergetics in Mouse Striatal Slices
by Msema Msackyi, Yuanxin Chen, Wangchen Tsering, Ninghan Wang and Hui Zhang
Int. J. Mol. Sci. 2024, 25(9), 4580; https://doi.org/10.3390/ijms25094580 - 23 Apr 2024
Viewed by 527
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Dopamine (DA) neurons in the substantia nigra pars compacta, which have axonal projections to the dorsal striatum (dSTR), degenerate in PD. In contrast, DA neurons in the ventral tegmental area, with axonal projections [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Dopamine (DA) neurons in the substantia nigra pars compacta, which have axonal projections to the dorsal striatum (dSTR), degenerate in PD. In contrast, DA neurons in the ventral tegmental area, with axonal projections to the ventral striatum, including the nucleus accumbens (NAcc) shell, are largely spared. This study aims to uncover the relative contributions of glycolysis and oxidative phosphorylation (OxPhos) to DA release in the striatum. We measured evoked DA release in mouse striatal brain slices using fast-scan cyclic voltammetry applied every two minutes. Blocking OxPhos resulted in a greater reduction in evoked DA release in the dSTR when compared to the NAcc shell, while blocking glycolysis caused a more significant decrease in evoked DA release in the NAcc shell than in the dSTR. Furthermore, when glycolysis was bypassed in favor of direct OxPhos, evoked DA release in the NAcc shell decreased by approximately 50% over 40 min, whereas evoked DA release in the dSTR was largely unaffected. These results demonstrate that the dSTR relies primarily on OxPhos for energy production to maintain evoked DA release, whereas the NAcc shell depends more on glycolysis. Consistently, two-photon imaging revealed higher oxidation levels of DA terminals in the dSTR than in the NAcc shell. Together, these findings partly explain the selective vulnerability of DA terminals in the dSTR to degeneration in PD. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegenerative Diseases)
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12 pages, 1651 KiB  
Article
HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND)
by Izchel Figarola-Centurión, Martha Escoto-Delgadillo, Gracia Viviana González-Enríquez, Juan Ernesto Gutiérrez-Sevilla, Eduardo Vázquez-Valls, Jhonathan Cárdenas-Bedoya and Blanca Miriam Torres-Mendoza
Int. J. Mol. Sci. 2023, 24(24), 17566; https://doi.org/10.3390/ijms242417566 - 17 Dec 2023
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Abstract
During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent [...] Read more.
During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague–Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegenerative Diseases)
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Review

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15 pages, 10056 KiB  
Review
The Role of Bioenergetics in Neurodegeneration
by Taylor A. Strope, Cole J. Birky and Heather M. Wilkins
Int. J. Mol. Sci. 2022, 23(16), 9212; https://doi.org/10.3390/ijms23169212 - 16 Aug 2022
Cited by 9 | Viewed by 2877
Abstract
Bioenergetic and mitochondrial dysfunction are common hallmarks of neurodegenerative diseases. Decades of research describe how genetic and environmental factors initiate changes in mitochondria and bioenergetics across Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Mitochondria control many cellular processes, including [...] Read more.
Bioenergetic and mitochondrial dysfunction are common hallmarks of neurodegenerative diseases. Decades of research describe how genetic and environmental factors initiate changes in mitochondria and bioenergetics across Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Mitochondria control many cellular processes, including proteostasis, inflammation, and cell survival/death. These cellular processes and pathologies are common across neurodegenerative diseases. Evidence suggests that mitochondria and bioenergetic disruption may drive pathological changes, placing mitochondria as an upstream causative factor in neurodegenerative disease onset and progression. Here, we discuss evidence of mitochondrial and bioenergetic dysfunction in neurodegenerative diseases and address how mitochondria can drive common pathological features of these diseases. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegenerative Diseases)
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18 pages, 1042 KiB  
Review
Role of Mitochondrial Dynamics in Cocaine’s Neurotoxicity
by Shuheng Wen, Toshihiko Aki, Takeshi Funakoshi, Kana Unuma and Koichi Uemura
Int. J. Mol. Sci. 2022, 23(10), 5418; https://doi.org/10.3390/ijms23105418 - 12 May 2022
Cited by 10 | Viewed by 4058
Abstract
The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as [...] Read more.
The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as one way it exerts its neurotoxicity, wherein the disturbances in mitochondrial dynamics have been suggested to play an essential role. In this review, we summarize the neurotoxicity of cocaine and the role of mitochondrial dynamics in cellular physiology. Subsequently, we introduce current findings that link disturbed neuronal mitochondrial dynamics with cocaine exposure. Finally, the possible role and potential therapeutic value of mitochondrial dynamics in cocaine neurotoxicity are discussed. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegenerative Diseases)
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Other

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16 pages, 2429 KiB  
Case Report
Mitochondrial and Endoplasmic Reticulum Alterations in a Case of Amyotrophic Lateral Sclerosis Caused by TDP-43 A382T Mutation
by Giada Zanini, Valentina Selleri, Milena Nasi, Anna De Gaetano, Ilaria Martinelli, Giulia Gianferrari, Francesco Demetrio Lofaro, Federica Boraldi, Jessica Mandrioli and Marcello Pinti
Int. J. Mol. Sci. 2022, 23(19), 11881; https://doi.org/10.3390/ijms231911881 - 6 Oct 2022
Cited by 6 | Viewed by 2209
Abstract
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients [...] Read more.
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegenerative Diseases)
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