Outstanding Questions in Mitophagy: What We Do and Do Not Know

Montava-Garriga, Lambert; Ganley, Ian G.

doi:10.1016/j.jmb.2019.06.032

Cited by 158 publications

(154 citation statements)

References 227 publications

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“…Cargo degradation by selective autophagy relies on autophagy receptors, which are LIR-containing proteins that facilitate interaction between a cargo (often ubiquitinated) and LC3/GA-BARAP in the autophagosomal membrane and themselves become degraded together with the cargo (Galluzzi et al, 2017). Autophagy receptors can be cytosolic proteins (such as p62, NBR1, or NDP52) or membrane-bound cargo-specific proteins (such as the mitochondria proteins BNIP3 and BNIP3L [BCL-interacting protein 3 and its ligand] and FUN14 domain-containing 1; Montava-Garriga and Ganley, 2020). The identification of cargo receptors initially offered a simple linear model of selective autophagy, in which cargo is recognized by specific autophagy receptors that further recruit LC3-containing phagophores to facilitate cargo sequestration.…”

Section: Autophagosome Biogenesis During Selective Autophagymentioning

confidence: 99%

Autophagosome biogenesis: From membrane growth to closure

Melia

Lystad

Simonsen

2020

Journal of Cell Biology

219

194

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Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding of the mechanisms involved in autophagosome biogenesis has increased substantially during the last 20 yr. Several key questions do remain open, however, including, What determines the site of autophagosome nucleation? What is the origin and lipid composition of the autophagosome membrane? How is cargo sequestration regulated under nonselective and selective types of autophagy? This review provides key insight into the core molecular mechanisms underlying autophagosome biogenesis, with a specific emphasis on membrane modeling events, and highlights recent conceptual advances in the field.

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Section: Autophagosome Biogenesis During Selective Autophagymentioning

confidence: 99%

Autophagosome biogenesis: From membrane growth to closure

Melia

Lystad

Simonsen

2020

Journal of Cell Biology

219

194

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“…In addition, mitophagy regulates the response to mitochondrial danger, for example, the appearance of mtDNA in the cytosol, which contributes to an increase in the inflammatory response. Defective mitophagy disrupts the immune response at the level of secretion of inflammatory cytokines, which leads to impaired normal functioning of immune cells and this contributes to the development of inflammatory and autoimmune diseases [137,138].…”

Section: Mitophagy and Mtdna Mutationsmentioning

confidence: 99%

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

Orekhov

Nikiforov

Ivanova

et al. 2020

JCM

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Chronification of inflammation is the process that lies at the basis of several human diseases that make up to 80% of morbidity and mortality worldwide. It can also explain a great deal of processes related to aging. Atherosclerosis is an example of the most important chronic inflammatory pathology in terms of public health impact. Atherogenesis is based on the inflammatory response of the innate immunity arising locally or focally. The main trigger for this response appears to be modified low-density lipoprotein (LDL), although other factors may also play a role. With the quick resolution of inflammation, atherosclerotic changes in the arterial wall do not occur. However, a violation of the innate immunity response can lead to chronification of local inflammation and, as a result, to atherosclerotic lesion formation. In this review, we discuss possible mechanisms of the impaired immune response with a special focus on mitochondrial dysfunction. Some mitochondrial dysfunctions may be due to mutations in mitochondrial DNA. Several mitochondrial DNA mutations leading to defective mitophagy have been identified. The regulatory role of mitophagy in the immune response has been shown in recent studies. We suggest that defective mitophagy promoted by mutations in mitochondrial DNA can cause innate immunity disorders leading to chronification of inflammation.

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“…The integration of mitochondrial biogenesis and selective degradation via mitophagy is essential for the preservation of healthy muscle, and disruption of this balance can result in alterations in muscle bioenergetics and loss of muscle mass and function (Hood, Memme, Oliveira, & Triolo, 2019). Mitophagy is regulated at numerous levels, and a number of distinct mitophagic pathways have been elucidated such as ubiquitin‐mediated mitophagy including the Pink/Parkin pathway and ubiquitin independent pathways via mitophagy receptors on the outer mitochondrial membrane (e.g., BNIP3), however, the exact regulatory mechanisms remain to be fully understood (for reviews, see Montava‐Garriga & Ganley, 2019; Palikaras, Lionaki, & Tavernarakis, 2018).…”

Section: Introductionmentioning

confidence: 99%

miR‐181a regulates p62/SQSTM1, parkin, and protein DJ‐1 promoting mitochondrial dynamics in skeletal muscle aging

et al. 2020

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One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR‐181a target interactions. Using functional approaches and mito‐QC assay, we have established that miR‐181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ‐1 in vitro. Downregulation of miR‐181a with age was associated with an accumulation of autophagy‐related proteins and abnormal mitochondria. Restoring miR‐181a levels in old mice prevented accumulation of p62, DJ‐1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.

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Outstanding Questions in Mitophagy: What We Do and Do Not Know

Cited by 158 publications

References 227 publications

Autophagosome biogenesis: From membrane growth to closure

Autophagosome biogenesis: From membrane growth to closure

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

miR‐181a regulates p62/SQSTM1, parkin, and protein DJ‐1 promoting mitochondrial dynamics in skeletal muscle aging

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