Mitophagy

Federal government websites often end in. The site is secure. Mitophagy is a selective autophagic process, mitophagy for cellular homeostasis, mitophagy, that eliminates dysfunctional mitochondria.

Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA mtDNA mutations, increased production of mitochondrial reactive oxygen species ROS and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies.

Mitophagy

Federal government websites often end in. The site is secure. Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy. Macroautophagy hereafter referred to as autophagy is a genetically programmed, evolutionarily conserved catabolic process that degrades cellular proteins, and damaged or excessive organelles through the formation of a double-membrane structure known as the autophagosome Mizushima, ; Nakatogawa et al. Autophagosomes then fuse with lysosomes to form autolysosomes where the enveloped contents are degraded. The important roles of these Atg complexes in regulating autophagy have been extensively reviewed Ravikumar et al. Although it was initially thought that autophagy was a non-selective bulk degradation pathway, it is now widely accepted that there are two types of autophagy, non-selective and selective.

It has been proposed that Sal promotes Parkin expression, activates mitophagy, scavenges ROS, and suppresses apoptosis mitophagy ], mitophagy. Drp1 has been shown to play a key role in cardiac function [ ].

Mitochondria are highly plastic and dynamic organelles that have graded responses to the changing cellular, environmental, and developmental cues. Mitochondria undergo constant mitochondrial fission and fusion, mitochondrial biogenesis, and mitophagy, which coordinately control mitochondrial morphology, quantity, quality, turnover, and inheritance. Mitophagy is a cellular process that selectively removes the aged and damaged mitochondria via the specific sequestration and engulfment of mitochondria for subsequent lysosomal degradation. It plays a pivotal role in reinstating cellular homeostasis in normal physiology and conditions of stress. Damaged mitochondria may either instigate innate immunity through the overproduction of ROS or the release of mtDNA, or trigger cell death through the release of cytochrome c and other apoptogenic factors when mitochondria damage is beyond repair. Distinct molecular machineries and signaling pathways are found to regulate these mitochondrial dynamics and behaviors. It is less clear how mitochondrial behaviors are coordinated at molecular levels.

Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA mtDNA mutations, increased production of mitochondrial reactive oxygen species ROS and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies. Mitochondria are highly organized and dynamic organelles that undergo continuous fission and fusion Chen and Chan, ; Pham et al. They originated from endosymbiotic proteobacteria and conferred substantial advantages for eukaryotic cells during evolution. On the other hand, like a double-edged sword, mitochondria can turn into a potential threat to cellular homeostasis and survival. Moreover, mitochondria are the major source of reactive oxygen species ROS.

Mitophagy

Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.

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Miro proteins prime mitochondria for Parkin translocation and mitophagy. It would be interesting to determine whether there is also a depletion of GSH levels under respiratory conditions or whether other antioxidants in addition to the GSH precursor NAC would also suppress Atg32 expression and mitophagy. In line with these observation, a large number of studies have shown that T2D is associated with the presence of damaged and swollen mitochondria accumulating in the retina, with partial crystolysis and impaired respiration [ , , , , , ]. Cell 17, 87— Cell 61, — NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Microtubule-associated protein 1 light chain 3 LC3 interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. Beyond autophagy: A novel role for autism-linked Wdfy3 in brain mitophagy. Some LRRK2 mutations in PD show increased kinase activity [ ], which activates the autophagy receptor p62 but decreases the number of lysosomes with an acidic pH, resulting in the accumulation of autophagosomes and impaired autophagy [ ]. Molecular Mechanisms of Mitophagy Mitophagy shares the core molecular machinery with general macroautophagy and can occur in an either selective or non-selective fashion Levine and Kroemer, The future could also bring new findings on novel, non-canonical mechanisms of mitochondrial quality control, such as the recently described mitochondrion-derived vesicles, characterized in hypoxic neurons and cardiomyocytes [ ]. In fertilized mouse embryos, many autophagy markers such as LC3, GABRAP, and p62 are found closely associated with paternal ubiquitin-positive mitochondria. PMID Wang Y. Iron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C.

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Cai Q. Free Radic. New Insights into the Role of inflammation in the pathogenesis of atherosclerosis. Aging It has been known that autophagy declines during aging, and the expression levels of many autophagy genes or related proteins such as Atg7, Atg5, Atg4B, and LAMP-2 decreases in the brains and liver of aging humans and mice Zhang and Cuervo, ; Lipinski et al. As mitochondria are essential organelles that regulate cellular energy metabolism and cell death, mitochondrial homeostasis has been linked to many pathophysiological conditions and diseases. Ischemic preconditioning: Protection against myocardial necrosis and apoptosis. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mitochondrial DNA stress primes the antiviral innate immune response. Hamacher-Brady A. Parkin promotes mitophagic cell death in adult hippocampal neural stem cells following insulin withdrawal. ER-phagy mediates selective degradation of endoplasmic reticulum independently of the core autophagy machinery. However, cells deficient of all Atg8 family members could still undergo mitophagy although the overall size of mitophagosomes is smaller Nguyen et al. In Nix-deficient mice, mitochondrial clearance in reticulocytes is significantly inhibited or retarded, suggesting that Nix is required for the selective elimination of mitochondria Schweers et al.