The pathways of mitophagy for quality control and clearance of mitochondria.
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TLDR
The relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration are discussed, in addition to the importance of identifying specific regulators ofMitophagy that ensure selective sequestration of mitochondria as cargo.Abstract:
Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.read more
Citations
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The autophagosome: origins unknown, biogenesis complex
TL;DR: It is proposed that the isolation membrane forms from the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and the role of ATG proteins and the vesicular trafficking machinery in autophagosome formation is proposed.
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PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity
Lesley A. Kane,Michael Lazarou,Adam I. Fogel,Yan Li,Koji Yamano,Shireen A. Sarraf,Soojay Banerjee,Richard J. Youle +7 more
TL;DR: PINK1 phosphorylates ubiquitin, which then binds to Parkin and activates its E3 ligase activity, leading to induction of selective autophagy of damaged mitochondria.
Journal ArticleDOI
Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.
Konstantinos Palikaras,Konstantinos Palikaras,Eirini Lionaki,Nektarios Tavernarakis,Nektarios Tavernarakis +4 more
TL;DR: In this Review, Tavernarakis and colleagues describe recent advances in delineating the molecular mechanisms that mediate mitophagy, and discuss the complex roles of this pathway in physiological and pathological contexts.
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Cargo recognition and degradation by selective autophagy
TL;DR: Different types of selective autophagy are discussed, emphasizing the role of ligand receptors and scaffold proteins in providing cargo specificity, and unanswered questions in the field are highlighted.
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The LIR motif - crucial for selective autophagy.
TL;DR: Comment on new insights on the interactions of LIR-containing proteins with members of the ATG8 protein family on the interaction of autophagy receptors to LC3-interacting region proteins anchored in the phagophore membrane.
References
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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
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Autophagy: Renovation of Cells and Tissues
Noboru Mizushima,Masaaki Komatsu +1 more
TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
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Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
TL;DR: It is shown that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells and this recruitment promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondira in the pathogenesis of Parkinson's disease.
Journal ArticleDOI
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
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TL;DR: The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
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A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine
TL;DR: The mitochondria provide a direct link between the authors' environment and their genes and the mtDNA variants that permitted their forbears to energetically adapt to their ancestral homes are influencing their health today.