Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes

Xu, Xinping; Kobayashi, Satoru; Chen, Kai; Timm, Derek; Volden, Paul A.; Huang, Yuan; Gulick, James; Yue, Zhenyu; Robbins, Jeffrey; Epstein, Paul N.; Liang, Qiangrong

doi:10.1074/jbc.m113.474650

Cited by 216 publications

(224 citation statements)

References 57 publications

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“…The present study demonstrated that the diabetic myocardium is associated with reduced expression of PINK1 and Parkin, suggesting that mitochondrial quality control via the PINK1/Parkin pathway is influenced. These results are consistent with a previous study, which indicated that mitophagy was reduced in diabetic hearts 58. This group also reported mitochondrial dysfunction and accumulation of dysfunctional mitochondria in the diabetic myocardium.…”

Section: Discussionsupporting

confidence: 93%

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

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Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG‐treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up‐regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20‐like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin‐mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

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Section: Discussionsupporting

confidence: 93%

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

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“…[33][34][35][36] In addition, elimination of damaged mitochondria by mitophagy was reported to be relatively deficient or decreased in the cardiac musculature of patients with diabetes. 37 Similarly, two mitophagy regulators, Pink1 and Parkin (the genes that are relevant in the pathogenesis of Parkinson disease), were found to be downregulated in cardiac and skeletal muscles in diabetic states. 37,38 In this study, we observed that most of the mitochondria within the injured tubules in STZinduced diabetic mice were fragmented and had a randomly disorganized cellular distribution (Figures 6F and 7B).…”

Section: Discussionmentioning

confidence: 99%

“…37 Similarly, two mitophagy regulators, Pink1 and Parkin (the genes that are relevant in the pathogenesis of Parkinson disease), were found to be downregulated in cardiac and skeletal muscles in diabetic states. 37,38 In this study, we observed that most of the mitochondria within the injured tubules in STZinduced diabetic mice were fragmented and had a randomly disorganized cellular distribution (Figures 6F and 7B). At the same time, the cellular autophagic vacuoles and mitophagy were reduced in tubules, indicating less efficient removal of damaged mitochondria and a compromised surveillance mechanism.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

241

251

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Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under highglucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/ mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or D-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of D-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, D-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest D-glucarate as a potential therapeutic agent for the amelioration of DKD.

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“…Despite the fact that cardiac complications are major causes of mortality in patients with diabetes mellitus, therapeutic conceptions to prevent diabetic myocardiopathy remain inaccessible due to only partial understanding of the underlying mechanisms (1,2). Diabetic cardiomyopathy was first recognized by Rubler et al in patients with diabetes (3).…”

Section: Introductionmentioning

confidence: 99%

Sequential changes in autophagy in diabetic cardiac fibrosis

Gao¹,

Yang²,

Dong³

et al. 2015

Molecular Medicine Reports

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Abstract. Autophagy is considered to be associated with cardiac fibrosis. However, whether autophagy accelerates or ameliorates fibrosis remains to be elucidated. In the present study, 36 rats were divided into two groups: Control rats and diabetic rats. The diabetic rats were established by feeding the animals a high fat diet combined with streptozotocin. From the two groups, six rats were sacrificed after 1, 6 and 7 months. Cardiac systolic functions were measured. The collagen volume fraction was calculated using Masson's trichome staining and the mRNA expression levels of type-I and type-III collagen were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to assess the levels of cardiac fibrosis. The protein contents of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (P62) were evaluated using western blotting, and the mRNA expression of Beclin 1 was measured using RT-qPCR, in order to assess autophagy. The results revealed that, in the diabetic rats, cardiac fibrosis developed and cardiac systolic function was reduced. In the hearts of the diabetic rats, the mRNA expression levels of collagen type I and III, and Beclin1 were upregulated; the ratio of the protein level of LC3-II/LC3-I was increased and the content of P62 was decreased. All the changes were aggravated as time increased. The changes in autophagy were correlated with those of cardiac fibrosis, suggesting that autophagy may have a synergistic role in diabetic cardiac fibrosis.

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Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes

Cited by 216 publications

References 57 publications

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Sequential changes in autophagy in diabetic cardiac fibrosis

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