Quality control of the mitochondrion

Ng, Matthew Yoke Wui; Wai, Timothy; Simonsen, Anne

doi:10.1016/j.devcel.2021.02.009

Cited by 217 publications

(174 citation statements)

References 341 publications

(400 reference statements)

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Section: Induce Mitophagy; Andmentioning

confidence: 99%

“…Examination of mitochondrial turnover in cardiac myocytes reveals a half-life of ∼6-17 days as evaluated by conventional pulse chase assays 24, 25 , and contemporary analyses with maturation of mitoTimer fluorophore reveals that mitochondrial turnover slows down in the aging heart 26 . While mitochondrial protein quality control may proceed via multiple pathways, 27 turnover of mitochondria requires the autophagy-lysosome pathway by mitophagy 18 . Indeed, impairment of global macro-autophagy with inducible adult-onset cardiac myocyte-specific ablation of ATG5 28 or ATG7 29 , proteins essential for early steps in autophagosome formation, induces cardiomyopathy with appearance of damaged mitochondria on ultrastructural analyses.…”

Section: Introductionmentioning

confidence: 99%

“…2 Whether basal mitophagy suppresses myocardial inflammatory signaling in the unstressed heart remains unknown. It is noteworthy that all currently defined mitophagy pathways are intrinsic to damaged mitochondria and recognize mitochondrial damage or dysfunction to facilitate lysosomal removal of damaged mitochondria via mitophagy or other mechanisms; 27 whereby participation of innate immune mechanisms in this process remains a missing piece of this conceptual framework. In this manuscript, we uncover evidence that TRAF2, an innate immunity effector that we have previously identified as a mediator of mitophagy in isolated cardiac myocytes, 30 acts as a first line of defense against cardiac myocyte cell death and myocardial inflammation by facilitating mitophagy and suppressing TLR9 expression, respectively, in vivo in the mammalian heart.…”

Section: Introductionmentioning

confidence: 99%

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TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Kovács

et al. 2021

Preprint

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Mitochondrial damage triggers cell death signaling with catastrophic consequences in long-lived and irreplaceable cells, such as cardiac myocytes. Sensing of leaked mitochondrial DNA upon mitochondrial damage is also a potent trigger of inflammation. Whether the innate immune response pathways monitor mitochondrial damage in mitochondria-rich cardiac myocytes to prevent inflammation and cell death, remains unknown. TRAF2, an adaptor protein downstream of innate immune receptors, localizes to the mitochondria in the unstressed heart, with increased mitochondrial targeting in cardiomyopathic human hearts and after cardiac ischemia-reperfusion injury in mice. Inducible cardiomyocyte-specific deletion of TRAF2 in young adult mice impairs mitophagy with rapid decline in mitochondrial quality, upregulates TLR9 expression in cardiac myocytes, and results in inflammation and cell death manifesting as a fulminant cardiomyopathy. Preventing TLR9-mediated mitochondrial DNA sensing and resultant inflammation provides a short-term reprieve from cardiomyopathy, but persistence of damaged mitochondria results in long-term recrudescence. Restoration of TRAF2, but not the E3 ubiquitin ligase deficient mutant improves mitochondrial quality and rescues cardiomyopathy to restore homeostasis. Thus, the innate immune response acts via TRAF2 as the first line of defense against mitochondrial damage by orchestrating homeostatic mitophagy to dampen myocardial inflammation and prevent cell death.

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Section: Induce Mitophagy; Andmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Kovács

et al. 2021

Preprint

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“…Autophagy plays an additional metabolic role via the process of mitophagy [86]. Mitochondria, referred to as the "powerhouses of the cell", are organelles that contain all the machinery required for oxidative phosphorylation and produce most of the cellular supply of ATP, the cell's main energy source [87].…”

Section: Autophagy In Neural Stem Cell Proliferation and Differentiationmentioning

confidence: 99%

Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Zapata‐Muñoz¹,

Villarejo‐Zori²,

Largo-Barrientos³

et al. 2021

CST

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Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association.

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“…If not repaired or removed in a timely manner, large numbers of damaged mitochondria will accumulate in the cell, increase cell burden, and cause loss of cellular function. In addition, the crucial role of mitochondria in apoptosis also requires that the quality of these organelles be strictly controlled to avoid cell death (Matthew et al, 2021). A cellular strategy known as mitophagy functions to remove damaged mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy in Antiviral Immunity

Wang

Zheng

Huang

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria are important organelles whose primary function is energy production; in addition, they serve as signaling platforms for apoptosis and antiviral immunity. The central role of mitochondria in oxidative phosphorylation and apoptosis requires their quality to be tightly regulated. Mitophagy is the main cellular process responsible for mitochondrial quality control. It selectively sends damaged or excess mitochondria to the lysosomes for degradation and plays a critical role in maintaining cellular homeostasis. However, increasing evidence shows that viruses utilize mitophagy to promote their survival. Viruses use various strategies to manipulate mitophagy to eliminate critical, mitochondria-localized immune molecules in order to escape host immune attacks. In this article, we will review the scientific advances in mitophagy in viral infections and summarize how the host immune system responds to viral infection and how viruses manipulate host mitophagy to evade the host immune system.

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Quality control of the mitochondrion

Cited by 217 publications

References 341 publications

TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Mitophagy in Antiviral Immunity

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