Impaired
            <scp>GAPDH</scp>
            ‐induced mitophagy contributes to the pathology of Huntington's disease

Hwang, Sun‐Hee; Disatnik, Marie‐Hélène; Mochly‐Rosen, Daria

doi:10.15252/emmm.201505256

Cited by 136 publications

(119 citation statements)

References 87 publications

(114 reference statements)

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“…In microautophagy, cytoplasmic cargo is directly trapped and engulfed through membrane invagination by lysosomes. Although it is believed to be a random process, recent evidence suggests that parts of mitochondria are also degraded through this mechanism 95 . CMA, on the other hand, specifically degrades cytosolic proteins with a KFERQ motif, by directly transferring them to lysosomes.…”

Section: The Role Of Autophagy During Aging Of the Heartmentioning

confidence: 99%

Aging and Autophagy in the Heart

Shirakabe

Ikeda

Sciarretta

et al. 2016

Circulation Research

372

273

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The aging population is increasing in developed countries. Since the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as “autophagy”) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by accumulation of misfolded proteins and dysfunctional organelles. On the other hand, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

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Section: The Role Of Autophagy During Aging Of the Heartmentioning

confidence: 99%

Aging and Autophagy in the Heart

Shirakabe

Ikeda

Sciarretta

et al. 2016

Circulation Research

372

273

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“…Mechanistically, iGAPDH signals the induction of direct engulfment of damaged mitochondria into lysosomes. However, expanded polyglutamine repeats (mutant Huntingtin) inhibit GAPDH-induced mitophagy through abnormal interaction with GAPDH [69]. Hwang et al reported a reduction in GAPDH-induced mitophagy in HD cell models due to the inactivation of GAPDH by polyglutamine expansion[69].…”

Section: Mitophagy In Neurodegeneration and Agingmentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun

et al. 2017

Neurochemistry International

304

183

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Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

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“…This process is mainly triggered by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), that gets inactivated by mHtt and thus losses its selective association with damaged mitochondria. Further, abnormal interaction of mitochondrial GAPDH with mHtt impeded GAPDH-mediated mitophagy, contributing to accumulation of damaged mitochondria and increased cell death [60]. Recent studies have reported that mHtt also curtails the maturation of SREBP and up regulates the expression of LXR and LXR-targeted genes (ABCG1, ABCG4, SREBP, ApoE and HMGCoA reductase) which further lowers both the synthesis and transport of cholesterol from astrocytes to neurons via ApoE [56].…”

Section: Huntington's Diseasementioning

confidence: 99%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

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Impaired GAPDH ‐induced mitophagy contributes to the pathology of Huntington's disease

Cited by 136 publications

References 87 publications

Aging and Autophagy in the Heart

Aging and Autophagy in the Heart

Mitophagy in neurodegeneration and aging

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

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