Mitochondrial dysfunction and mitophagy defect triggered by heterozygous <i>GBA</i> mutations

Li, Hongyu; Ham, Ahrom; Ma, Thong; Kuo, Sheng Han; Kanter, Ellen; Kim, Dong-Hoon; Ko, Han Seok; Quan, Yi; Sardi, S. Pablo; Li, Aiqun; Arancio, Ottavio; Kang, Un Jung; Sulzer, David; Tang, Guping

doi:10.1080/15548627.2018.1509818

Cited by 160 publications

(113 citation statements)

References 81 publications

(87 reference statements)

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“…During erythrocyte maturation, NIX is essential for mitochondrial clearance, where mitophagy plays a developmental role. Autophagosome can recognize target mitochondria through LC3 adapters (in ubiquitin‐dependent and ubiquitin‐independent manners) and the direct interaction of LC3 with its receptors …”

Section: Mitophagy In Mammalsmentioning

confidence: 99%

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Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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Section: Mitophagy In Mammalsmentioning

confidence: 99%

“…Autophagosome can recognize target mitochondria through LC3 adapters (in ubiquitin-dependent and ubiquitin-independent manners) and the direct interaction of LC3 with its receptors. 34…”

Section: Mitophagy In Mammal Smentioning

confidence: 99%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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“…Whereas homozygous GBA mutation cause Gaucher disease (GD), GBA heterozygosity is a potential risk factor for developing PD with an earlier age of onset and a major risk to develop dementia compared to idiopathic PD [17]. Moreover, recent studies showed that GBA heterozygous mutation is linked with dysfunction in mitophagy [18,19].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

2019

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Parkinson's disease (PD) is associated with brain mitochondrial dysfunction. High-energy phosphates (HEPs), which rely on mitochondrial functioning, may be considered potential biomarkers for PD. Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) is a suitable tool to explore in vivo cerebral energetics. We considered 10 31 P-MRS studies in order to highlight the main findings about brain energetic compounds in patients affected by idiopathic PD and genetic PD. The studies investigated several brain areas such as frontal lobes, occipital lobes, temporoparietal cortex, visual cortex, midbrain, and basal ganglia. Resting-state studies reported contrasting results showing decreased as well as normal or increased HEPs levels in PD patients. Functional studies revealed abnormal PCr + βATP levels in PD subjects during the recovery phase and abnormal values at rest, during activation and recovery in one PD subject with PINK1 gene mutation suggesting that mitochondrial machinery is more impaired in PD patients with PINK1 gene mutation. PD is characterized by energetics impairment both in idiopathic PD as well as in genetic PD, suggesting that mitochondrial dysfunction underlies the disease. Studies are still sparse and sometimes contrasting, maybe due to different methodological approaches. Further studies are needed to better assess the role of mitochondria in the PD development.

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“…We have previously shown that ECSIT is ubiquitinated upon induction of mitochondrial depolarization by CCCP in macrophages and is a substrate for ubiquitination by Parkin 27 . Although mitophagy can be acutely triggered by mitochondrial damage, constant basal mitophagy to enable mitochondrial turnover has also been observed in macrophages 27 and brain tissues 12, 22, 46, 49, 50 . In primary neurons, we found that Ecsit deletion caused upregulation of Parkin (Fig.…”

Section: Resultsmentioning

confidence: 99%

ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

Lepelley

Vaughn

Staniszewski

et al. 2020

Preprint

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Altered mitochondrial fitness is a potential triggering factor in Alzheimer’s disease (AD). Mitochondrial quality control pathways are dysfunctional and mitochondrially-derived reactive oxygen species (mROS) levels are increased in AD patient brains. However, the pathways responsible for dysregulated mROS accumulation have remained relatively unclear. In this study, we demonstrate that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains. Neuronal ECSIT downregulation increased mROS generation and impaired mitophagy of defective mitochondria. Consequently, decreasing neuronal ECSIT caused AD-like changes, including memory loss and neuropathology. In contrast, augmented neuronal expression of ECSIT protected against the development of an AD-like phenotype. Decreased levels of ECSIT in AD patient brains therefore likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.

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Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Cited by 160 publications

References 81 publications

Mechanisms and roles of mitophagy in neurodegenerative diseases

Mechanisms and roles of mitophagy in neurodegenerative diseases

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

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