scholarly journals Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1065 ◽  
Author(s):  
Manohar Kodavati ◽  
Haibo Wang ◽  
Muralidhar L. Hegde
Keyword(s):  
Mitochondrial Dna ◽  
Dna Binding ◽  
Motor Neuron ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Motor Neuron Diseases ◽  
Potential Implication ◽  
Fused In Sarcoma ◽  
Apoptotic Pathways

Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.

scholarly journals Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

2016 ◽  
Vol 113 (51) ◽  
pp. E8316-E8325 ◽  
Author(s):  
Melanie Lalancette-Hebert ◽  
Aarti Sharma ◽  
Alexander K. Lyashchenko ◽  
Neil A. Shneider
Keyword(s):  
Motor Neuron ◽  
Mouse Models ◽  
Motor Neurons ◽  
Muscle Spindles ◽  
Excitatory Input ◽  
Synaptic Excitation ◽  
Fused In Sarcoma ◽  
Alpha Motor Neuron ◽  
Lateral Sclerosis

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IAactivation by targeted reduction of γ-MNs in SOD1G93Amutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.

scholarly journals Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Daniela M. Arduíno ◽  
A. Raquel Esteves ◽  
Sandra M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Growing Body ◽  
Parkinsonian Disorders ◽  
Mitochondrial Trafficking

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

The Role of Mitochondria in Systemic Lupus Erythematosus: A Glimpse of Various Pathogenetic Mechanisms

2020 ◽  
Vol 27 (20) ◽  
pp. 3346-3361 ◽  
Author(s):  
Shi-Kun Yang ◽  
Hao-Ran Zhang ◽  
Shu-Peng Shi ◽  
Ying-Qiu Zhu ◽  
Na Song ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mitochondrial Dysfunction ◽  
Lupus Erythematosus ◽  
Mitochondrial Dynamics ◽  
Therapeutic Targets ◽  
High Recurrence Rate ◽  
Systemic Lupus ◽  
Inflammatory Reactions ◽  
Novel Therapeutic

Background: Systemic Lupus Erythematosus (SLE) is a polysystem autoimmune disease that adversely affects human health. Various organs can be affected, including the kidney or brain. Traditional treatment methods for SLE primarily rely on glucocorticoids and immunosuppressors. Unfortunately, these therapeutic agents cannot prevent a high recurrence rate after SLE remission. Therefore, novel therapeutic targets are urgently required. Methods: A systematic search of the published literature regarding the abnormal structure and function of mitochondria in SLE and therapies targeting mitochondria was performed in several databases. Results: Accumulating evidence indicates that mitochondrial dysfunction plays important roles in the pathogenesis of SLE, including influencing mitochondrial DNA damage, mitochondrial dynamics change, abnormal mitochondrial biogenesis and energy metabolism, mitophagy, oxidative stress, inflammatory reactions, apoptosis and NETosis. Further investigation of mitochondrial pathophysiological roles will result in further clarification of SLE. Specific lupus-induced organ damage also exhibits characteristic mitochondrial changes. Conclusion: This review aimed to summarize the current research on the role of mitochondrial dysfunction in SLE, which will necessarily provide potential novel therapeutic targets for SLE.

Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss

2007 ◽  
Vol 226 (1-2) ◽  
pp. 185-193 ◽  
Author(s):  
Tatsuya Yamasoba ◽  
Shinichi Someya ◽  
Chikako Yamada ◽  
Richard Weindruch ◽  
Tomas A. Prolla ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Mitochondrial dynamics and mitochondrial dysfunction in mesenteric artery: role of homocysteine (867.11)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Anastasia Familtseva ◽  
Anuradha Kalani ◽  
Pradip Kamat ◽  
Neetu Tyagi ◽  
Suresh Tyagi
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mesenteric Artery ◽  
Mitochondrial Dynamics

scholarly journals A review: Management of motor neuron diseases

2022 ◽  
Vol 7 (4) ◽  
pp. 292-294
Author(s):  
Aarti Chopra ◽  
Ravi Kumar ◽  
Girendra Kumar Gautam
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Age At Onset ◽  
Motor Neuron Diseases ◽  
Progressive Degeneration ◽  
Review Management ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Motor neuron diseases are a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. These might affect the upper motor neurons, lower motor neurons, or both. The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. Amyotrophic lateral sclerosis (ALS) has been documented to be fatal within three years of onset. This activity focuses on amyotrophic lateral sclerosis as the prototype of MND, which affects both the upper and the lower motor neurons and discusses the role of inter-professional team in the differential diagnosis, evaluation, treatment, and prognostication. It also discusses various other phenotypes of MND with an emphasis on their distinguishing features in requisite detail.

Role of Mitochondrial Dysfunction in the Ca2+-Induced Decline of Transmitter Release at K+-Depolarized Motor Neuron Terminals

1999 ◽  
Vol 81 (2) ◽  
pp. 498-506 ◽  
Author(s):  
Michelle A. Calupca ◽  
Gregory M. Hendricks ◽  
Jean C. Hardwick ◽  
Rodney L. Parsons
Keyword(s):  
Motor Neuron ◽  
Mitochondrial Dysfunction ◽  
Transmitter Release ◽  
Synaptic Vesicles ◽  
Prolonged Exposure ◽  
Nerve Terminals ◽  
Atp Production ◽  
Neuron Terminals ◽  
Nerve Muscle

Role of mitochondrial dysfunction in the Ca2+-induced decline of transmitter release at K+-depolarized motor neuron terminals. The present study tested whether a Ca2+-induced disruption of mitochondrial function was responsible for the decline in miniature endplate current (MEPC) frequency that occurs with nerve-muscle preparations maintained in a 35 mM potassium propionate (35 mM KP) solution containing elevated calcium. When the 35 mM KP contained control Ca2+(1 mM), the MEPC frequency increased and remained elevated for many hours, and the mitochondria within twitch motor neuron terminals were similar in appearance to those in unstimulated terminals. All nerve terminals accumulated FM1–43 when the dye was present for the final 6 min of a 300-min exposure to 35 mM KP with control Ca2+. In contrast, when Ca2+ was increased to 3.6 mM in the 35 mM KP solution, the MEPC frequency initially reached frequencies >350 s− 1 but then gradually fell approaching frequencies <50 s−1. A progressive swelling and eventual distortion of mitochondria within the twitch motor neuron terminals occurred during prolonged exposure to 35 mM KP with elevated Ca2+. After ∼300 min in 35 mM KP with elevated Ca2+, only 58% of the twitch terminals accumulated FM1–43. The decline in MEPC frequency in 35 mM KP with elevated Ca2+ was less when 15 mM glucose was present or when preparations were pretreated with 10 μM oligomycin and then bathed in the 35 mM KP with glucose. When glucose was present, with or without oligomycin pretreatment, a greater percentage of twitch terminals accumulated FM1–43. However, the mitochondria in these preparations were still greatly swollen and distorted. We propose that prolonged depolarization of twitch motor neuron terminals by 35 mM KP with elevated Ca2+ produced a Ca2+-induced decrease in mitochondrial ATP production. Under these conditions, the cytosolic ATP/ADP ratio was decreased thereby compromising both transmitter release and refilling of recycled synaptic vesicles. The addition of glucose stimulated glycolysis which contributed to the maintenance of required ATP levels.

scholarly journals Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

2013 ◽  
Vol 305 (4) ◽  
pp. H459-H476 ◽  
Author(s):  
Emanuele Marzetti ◽  
Anna Csiszar ◽  
Debapriya Dutta ◽  
Gauthami Balagopal ◽  
Riccardo Calvani ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cardiovascular System ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Late Life ◽  
Age Related ◽  
Functional Consequences ◽  
Cardiovascular Aging ◽  
The Life Course

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD.

scholarly journals Revisiting the role of mitochondria in spinal muscular atrophy

2021 ◽  
Author(s):  
Rachel James ◽  
Helena Chaytow ◽  
Leire M. Ledahawsky ◽  
Thomas H. Gillingwater
Keyword(s):  
Nervous System ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Neurodegenerative Disorders ◽  
Autosomal Recessive ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Clinical Severity ◽  
Motor Neuron Diseases

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor neuron 1 (SMN1) gene. Despite its name, SMN is a ubiquitous protein that functions within and outside the nervous system and has multiple cellular roles in transcription, translation, and proteostatic mechanisms. Encouragingly, several SMN-directed therapies have recently reached the clinic, albeit this has highlighted the increasing need to develop combinatorial therapies for SMA to achieve full clinical efficacy. As a subcellular site of dysfunction in SMA, mitochondria represents a relevant target for a combinatorial therapy. Accordingly, we will discuss our current understanding of mitochondrial dysfunction in SMA, highlighting mitochondrial-based pathways that offer further mechanistic insights into the involvement of mitochondria in SMA. This may ultimately facilitate translational development of targeted mitochondrial therapies for SMA. Due to clinical and mechanistic overlaps, such strategies may also benefit other motor neuron diseases and related neurodegenerative disorders.

scholarly journals ROLE OF MITOCHONDRIAL DISFUNCTION IN THE DEVELOPMENT OF ALZHEIMER’S DISEASE

2021 ◽  
Vol 67 (1) ◽  
pp. 57-66
Author(s):  
V.V. Ganzha ◽  
◽  
E.A. Lukyanetz ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Tau Protein ◽  
Mitochondrial Dynamics ◽  
Memory Loss ◽  
Disease Process ◽  
Hyperphosphorylated Tau Protein ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intensive research have shown that multicellular changes are involved in AD’s development and progression, including mitochondrial damage, synaptic dysfunction, formation and accumulation of beta-amyloid (Aβ), formation and accumulation of hyperphosphorylated tau protein, and loss of neurons in patients with this disease. Among them, mitochondrial dysfunction and synaptic damage are the primary manifestations in the disease process. Recent studies have also shown that defective mitophagy caused by Aβ and tau protein are the main indicators in AD’s pathogenesis. This review includes an overview of recent researches on the role of mitochondria in AD development. The review summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics, changes in mitochondrial DNA, and calcium dyshomeostasis in AD pathogenesis

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