Deciphering the Molecular Signals of PINK1/Parkin Mitophagy

Nguyen, Thanh Ngoc; Padman, Benjamin Scott; Lazarou, Michael

doi:10.1016/j.tcb.2016.05.008

Cited by 534 publications

(378 citation statements)

References 90 publications

(157 reference statements)

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“…PINK1 accumulates on the surface of dysfunctional mitochondria where it simultaneously recruits and activates the E3 ubiquitin ligase activity of Parkin. Parkin ubiquitylates itself and other outer mitochondrial membrane proteins that serve as binding partners of p62, an adaptor molecule that interacts with LC3 to culminate in the engulfment of damaged mitochondria within autophagosomes for degradation 188,189 . PINK1 also has a crucial role in the maintenance of mitochondrial morphology and function, thus models of PINK1 deficiency result in impaired electron transport chain function, altered mitochondrial fusion-fission dynamics, increased oxidative stress and insufficient mitophagy 190 .…”

Section: Targets and Therapeutic Interventions For Mitochondrial Damagementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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Section: Targets and Therapeutic Interventions For Mitochondrial Damagementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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“…Under healthy conditions, Parkin has been proposed to protect dopaminergic neurons by promoting mitochondrial homeostasis in a PGC-1α-dependent manner (Zheng et al, 2017). Furthermore, Mfn2 has been reported to function as a receptor for Parkin in cardiac cells (Chen & Dorn, 2013;Gong et al, 2015), however whether this extends beyond this cell type is unclear (Narendra et al, 2008;Nguyen et al, 2016). Overall, these data provide a significant link between Mfn2 regulation and PD.…”

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 88%

“…Mutations in two mitochondrial genes, PINK1 and Parkin, are causal for hereditary PD, linking mitochondrial dysfunction to this disease (Kitada et al, 1998;Valente et al, 2004;Dodson & Guo, 2007). Mfn2 is a key ubiquitination target of Parkin (Matsuda et al, 2010;Nguyen, Padman & Lazarou, 2016), and Parkin mediates the expression of PGC-1α (Shin et al, 2011), which in turn controls Mfn2 expression under stress conditions (see Section IV) (Bach et al, 2003Soriano et al, 2006). Under healthy conditions, Parkin has been proposed to protect dopaminergic neurons by promoting mitochondrial homeostasis in a PGC-1α-dependent manner (Zheng et al, 2017).…”

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

Self Cite

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Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

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“…Many of these diverse receptors are known to interact with LC3B, the classical marker of the autophagic membrane, via LC3-interacting region (LIR) motifs, as mentioned above [55]. For example, the identification of clearly defined roles for the mitochondrial cargo receptors NDP52 and optineurin have provided exciting new insights into the selective process of mitophagy [56,57]. In addition to NDP52 [58], which may play roles in other types of autophagy such as xenophagy [59], general candidate receptors for the targeted turnover of other cellular organelles have also been identified, including p62/SQSTM1, NBR1, and Huntingtin [60–62].…”

Section: Proteins Involved In Lipophagy Inductionmentioning

confidence: 99%

Breaking fat: The regulation and mechanisms of lipophagy

Schulze

Sathyanarayan

Mashek

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

189

115

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Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). While the field of lipophagy research is relatively young, an expansion of research in this area over the past several years has greatly advanced our understanding of lipophagy. Since its original characterization in fasted liver, the contribution of lipophagy is now recognized in various organisms, cell types, metabolic states and disease models. Moreover, recent studies provide exciting new insights into the underlying mechanisms of lipophagy induction as well as the consequences of lipophagy on cell metabolism and signaling. This review summarizes recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as our understanding of lipophagy continues to grow and evolve.

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Deciphering the Molecular Signals of PINK1/Parkin Mitophagy

Cited by 534 publications

References 90 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Structure, function, and regulation of mitofusin‐2 in health and disease

Breaking fat: The regulation and mechanisms of lipophagy

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