Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice

Woodall, Benjamin P.; Orogo, Amabel M.; Najor, Rita H.; Cortez, Melissa Q.; Moreno, Eileen R.; Wang, Hongxia; Divakaruni, Ajit S.; Murphy, Anne N.; Gustafsson, Åsa B.

doi:10.1172/jci.insight.127713

Cited by 43 publications

(47 citation statements)

References 50 publications

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“…Parkin deficiency inhibits postnatal mitochondrial maturation that is critical to survival (14). Parkin levels were downregulated on cardiac disorders such as I/R injury (24), hypoxia injury (44), diabetic cardiomyopathy (57), myocardial aging, and cardiac hypertrophy (58). Parkin reduction participates in cardiac pathological process, but the underlying mechanism is not known (20,23,24).…”

Section: Introductionmentioning

confidence: 99%

Parkin Regulates Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury by Targeting Cyclophilin-D

Sun

Ding

et al. 2019

Antioxidants & Redox Signaling

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Aims: Cardiomyocyte death critically contributes to the pathogenesis of cardiac disorders, such as myocardial infarction, heart failure, and cardiac ischemia/reperfusion (I/R) injury. As one of the main forms of cardiac cell death, necrosis plays a critical role in heart diseases. Multiple signaling pathways of necrosis have been demonstrated, in which death receptors, receptor-interacting serine/threonine-protein 1 and 3 kinases, and cyclophilin-D (CypD) have been deeply implicated. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondrial permeability transition pore (mPTP)-CypD-dependent death pathway, is poorly understood. Parkin functions as an E3 ubiquitin protein ligase that mainly mediates mitophagy cascades. As yet, it is not clear whether Parkin participates in regulating necrosis and myocardial I/R injury. Results: Here, our results showed that Parkin mediated mitophagy and inhibited necrosis under oxidative stress. In further exploring the underlying mechanisms, we found that Parkin suppressed mPTP opening by catalyzing the ubiquitination of CypD in necrotic cascades, which were not involved in Parkin-regulated mitophagy. Parkin inhibited necrosis, reduced myocardial I/R injury, and improved cardiac function. Innovation: Our present work reveals a highlighted connection between the mitochondrial matrix-localized Parkin and the mPTP-CypD-dependent necrotic signaling pathway in cardiac injury. Conclusion: Our results revealed a novel myocardial necrotic regulating model composed of Parkin, CypD, and mPTP, which may provide potential therapeutic targets and strategies to modulate the levels of these molecules.

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Section: Introductionmentioning

confidence: 99%

Parkin Regulates Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury by Targeting Cyclophilin-D

Sun

Ding

et al. 2019

Antioxidants & Redox Signaling

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“…Zha et al showed that the advanced glycation end products treatment increased the activation of PINK1/Parkinmediated mitophagy in the process of cardiomyocyte senescence, thus inhibition of mitophagy might be a promising approach to block the senescent state in cardiomyocytes (Zha et al, 2017). In addition, Woodall et al suggested that Parkin is dispensable for mitochondrial quality control in a mtDNA mutation mice model of cardiac aging (Woodall et al, 2019). Zhou et al reported that melatonin may activate AMPKa to suppress mitophagy and protect cardiac microvasculature against IR injury (Zhou et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Gerontoxanthone I and Macluraxanthone Induce Mitophagy and Attenuate Ischemia/Reperfusion Injury

Xiang

Zhang

et al. 2020

Front. Pharmacol.

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Mitophagy is a crucial process in controlling mitochondrial biogenesis. Balancing mitophagy and mitochondrial functions is required for maintaining cellular homeostasis. In this study, we found that Gerontoxanthone I (GeX1) and Macluraxanthone (McX), xanthone derivatives isolated from Garcinia bracteata C. Y. Wu ex Y. H. Li, induced Parkin puncta accumulation and promoted mitophagy. GeX1 and McX treatment induced the degradation of mitophagy-related proteins such as Tom20 and Tim23. GeX1 and McX directly stabilized PTEN-induced putative kinase 1 (PINK1) on the outer membrane of the mitochondria, and then recruited Parkin to mitochondria. This significantly induced phosphorylation and ubiquitination of Parkin, suggesting that GeX1 and McX mediate mitophagy through the PINK1-Parkin pathway. Transfecting ParkinS65A or pretreated MG132 abolished the induction effects of GeX1 and McX on mitophagy. Furthermore, GeX1 and McX treatment decreased cell death and the level of ROS in an ischemia/ reperfusion (IR) injury model in H9c2 cells compared to a control group. Taken together, our data suggested that GeX1 and McX induce PINK1-Parkin-mediated mitophagy and attenuate myocardial IR injury in vitro.

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“…These studies present evidence that enhancing mitophagy by targeting the Parkin pathway is beneficial. However, the antiaging effect of Parkin is likely dose-dependent as aged transgenic mice with higher levels of Parkin overexpression develop cardiac fibrosis likely due to an imbalance between ubiquitination and autophagic degradation (66).…”

Section: Mitophagy and Agingmentioning

confidence: 99%

“…A mouse model carrying a proofreadingdefective mtDNA polymerase γ (POLG) accumulate mtDNA mutations which leads to accelerated aging (67). Unexpectedly, Parkin plays a minimal role in clearing cardiac mitochondria in POLG mice as cardiac aging is unaffected by cardiacspecific overexpression or global deletion of Parkin (66). Instead, hearts in aged POLG mice have elevated levels of the mitophagy receptor BNIP3 coupled with enhanced mitochondrial biogenesis, indicating enhanced baseline mitochondrial turnover (66).…”

Section: Mitophagy and Agingmentioning

confidence: 99%

“…Unexpectedly, Parkin plays a minimal role in clearing cardiac mitochondria in POLG mice as cardiac aging is unaffected by cardiacspecific overexpression or global deletion of Parkin (66). Instead, hearts in aged POLG mice have elevated levels of the mitophagy receptor BNIP3 coupled with enhanced mitochondrial biogenesis, indicating enhanced baseline mitochondrial turnover (66). The fact that NIX/BNIP3 double knockout mice accumulate dysfunctional mitochondria in the heart at an accelerated rate with age compared to wild type mice confirms that these mitophagy receptors play a key role in baseline mitochondrial maintenance (68).…”

Section: Mitophagy and Agingmentioning

confidence: 99%

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The Aging Heart: Mitophagy at the Center of Rejuvenation

Liang

Gustafsson

2020

Front. Cardiovasc. Med.

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Aging is associated with structural and functional changes in the heart and is a major risk factor in developing cardiovascular disease. Many recent studies have focused on increasing our understanding of the basis of aging at the cellular and molecular levels in various tissues, including the heart. It is known that there is an age-related decline in cellular quality control pathways such as autophagy and mitophagy, which leads to accumulation of potentially harmful cellular components in cardiac myocytes. There is evidence that diminished autophagy and mitophagy accelerate the aging process, while enhancement preserves cardiac homeostasis and extends life span. Here, we review the current knowledge of autophagy and mitophagy in aging and discuss how age-associated alterations in these processes contribute to cardiac aging and age-related cardiovascular diseases.

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Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice

Cited by 43 publications

References 50 publications

Parkin Regulates Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury by Targeting Cyclophilin-D

Parkin Regulates Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury by Targeting Cyclophilin-D

Gerontoxanthone I and Macluraxanthone Induce Mitophagy and Attenuate Ischemia/Reperfusion Injury

The Aging Heart: Mitophagy at the Center of Rejuvenation

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