scholarly journals Mitochondrial Dysfunctions in Neurodegenerative Diseases: Relevance to Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jana Hroudová ◽  
Namrata Singh ◽  
Zdeněk Fišar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Electron Transport ◽  
Neurodegenerative Diseases ◽  
Electron Transport Chain ◽  
Nuclear Dna ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Dysfunctions ◽  
Transport Chain

Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

P1-075: Association of genetic variation in the electron transport chain and Alzheimer's disease

2010 ◽  
Vol 6 ◽  
pp. S195-S196
Author(s):  
Ryan M. Huebinger ◽  
Kirk Wilhelmsen ◽  
Ramon Diaz-Arrastia ◽  
Scott Chasse ◽  
Sid E. O'Bryant ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Transport Chain

scholarly journals Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1587
Author(s):  
Pamela J. Yao ◽  
Erden Eren ◽  
Edward J. Goetzl ◽  
Dimitrios Kapogiannis
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Catalytic Activity ◽  
Electron Transport ◽  
Mitochondrial Dysfunction ◽  
Extracellular Vesicles ◽  
Atp Synthase ◽  
Electron Transport Chain ◽  
Control Subjects ◽  
Transport Chain

Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer’s disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction in AD is reflected in ETC and SOD1 levels and activity in plasma neuron-derived extracellular vesicles (NDEVs). We immunoprecipitated NDEVs targeting neuronal marker L1CAM from two cohorts: one including 22 individuals with early AD and 29 control subjects; and another including 14 individuals with early AD and 14 control subjects. In the first cohort, we measured levels of complexes I, III, IV, ATP synthase, and SOD1; in the second cohort, we measured levels and catalytic activity of complexes IV and ATP synthase. AD individuals had lower levels of complexes I (p < 0.0001), III (p < 0.0001), IV (p = 0.0061), and V (p < 0.0001), and SOD1 (p < 0.0001) compared to controls. AD individuals also had lower levels of catalytic activity of complex IV (p = 0.0214) and ATP synthase (p < 0.0001). NDEVs confirm quantitative and functional abnormalities in ECT complexes and SOD1 previously observed in AD models and during autopsy, opening the way for using them as biomarkers for mitochondrial dysfunction in AD.

Electron transport chain defects in Alzheimer's disease brain

Neurology ◽  
1994 ◽  
Vol 44 (6) ◽  
pp. 1090-1090 ◽  
Author(s):  
W. D. Parker ◽  
J. P. BA ◽  
C. M. Filley ◽  
B. K. Kleinschmidt-DeMasters
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Transport Chain ◽  
Chain Defects

scholarly journals Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 961 ◽  
Author(s):  
Darryll Oliver ◽  
P. Reddy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Cell Cultures ◽  
Neuronal Damage ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Large Family ◽  
Related Protein

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

2018 ◽  
Vol 46 (4) ◽  
pp. 891-909 ◽  
Author(s):  
Ruby Macdonald ◽  
Katy Barnes ◽  
Christopher Hastings ◽  
Heather Mortiboys
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Central Mechanism ◽  
Phenotypic Screening ◽  
Mitochondrial Abnormalities

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

scholarly journals Identifying the Effects of Reactive Oxygen Species on Mitochondrial Dynamics and Cytoskeleton Stability in Dictyostelium discoideum

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2147
Author(s):  
Evan Downs ◽  
Amber D. Bottrell ◽  
Kari Naylor
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Dictyostelium Discoideum ◽  
Mitochondrial Dynamics ◽  
Reactive Oxygen ◽  
Oxygen Species

Defects in mitochondrial dynamics, fission, fusion, and motility have been implicated in the pathogenesis of multiple neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Charcot–Marie–Tooth disease. Another key feature of neurodegeneration is the increase in reactive oxygen species (ROS). Previous work has shown that the cytoskeleton, in particular the microtubules, and ROS generated by rotenone significantly regulate mitochondrial dynamics in Dictyostelium discoideum. The goal of this project is to study the effects of ROS on mitochondrial dynamics within our model organism D. discoideum to further understand the underlying issues that are the root of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We chose three likely ROS inducers, cumene hydroperoxide, hydroxylamine hydrochloride, and Antimycin A. Our work demonstrates that alteration of the microtubule cytoskeleton is not required to alter dynamics in response to ROS and there is no easy way to predict how mitochondrial dynamics will be altered based on which ROS generator is used. This research contributes to the better understanding of the cellular mechanisms that induce the pathogenesis of incurable neurodegenerative diseases with the hope that it will translate into developing new and more effective treatments for patients afflicted by them.

scholarly journals CofActor: A light- and stress-gated optogenetic clustering tool to study disease-associated cytoskeletal dynamics in living cells

2020 ◽  
Vol 295 (32) ◽  
pp. 11231-11245
Author(s):  
Fatema B. Salem ◽  
Wyatt P. Bunner ◽  
Vishwanath V. Prabhu ◽  
Abu-Bakarr Kuyateh ◽  
Collin T. O'Bryant ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Early Stage ◽  
Cellular Stress ◽  
Reactive Oxygen ◽  
Atp Depletion ◽  
Oxygen Species

The hallmarks of neurodegenerative diseases, including neural fibrils, reactive oxygen species, and cofilin–actin rods, present numerous challenges in the development of in vivo diagnostic tools. Biomarkers such as β-amyloid (Aβ) fibrils and Tau tangles in Alzheimer's disease are accessible only via invasive cerebrospinal fluid assays, and reactive oxygen species can be fleeting and challenging to monitor in vivo. Although remaining a challenge for in vivo detection, the protein–protein interactions underlying these disease-specific biomarkers present opportunities for the engineering of in vitro pathology-sensitive biosensors. These tools can be useful for investigating early stage events in neurodegenerative diseases in both cellular and animal models and may lead to clinically useful reagents. Here, we report a light- and cellular stress–gated protein switch based on cofilin–actin rod formation, occurring in stressed neurons in the Alzheimer's disease brain and following ischemia. By coupling the stress-sensitive cofilin–actin interaction with the light-responsive Cry2-CIB blue-light switch, referred to hereafter as the CofActor, we accomplished both light- and energetic/oxidative stress–gated control of this interaction. Site-directed mutagenesis of both cofilin and actin revealed residues critical for sustaining or abrogating the light- and stress-gated response. Of note, the switch response varied depending on whether cellular stress was generated via glycolytic inhibition or by both glycolytic inhibition and azide-induced ATP depletion. We also demonstrate light- and cellular stress–gated switch function in cultured hippocampal neurons. CofActor holds promise for the tracking of early stage events in neurodegeneration and for investigating actin's interactions with other proteins during cellular stress.

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