Increasing Fatty Acid Oxidation Prevents High-Fat Diet–Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy

Shao, Dan; Kolwicz, Stephen C.; Wang, Pei; Roe, Nathan D.; Villet, Outi; Nishi, Kiyoto; Hsu, Yun-Wei A.; Flint, Galina; Caudal, Arianne; Wang, Wang; Regnier, Michael; Tian, Rong

doi:10.1161/circulationaha.119.043319

Cited by 142 publications

(119 citation statements)

References 55 publications

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“…Diet induced obesity increases triglyceride storage in multiple tissues causing lipotoxicity that can alter mitochondrial architecture and function, inducing swelling with reduced cristae density (33, 34) . EM revealed such mitochondrial changes as well as myocardial lipid accumulation in both OVX and male mice treated with placebo, and both features improved with PDE9-I (Figure 4f, Figure S5a, S5b).…”

Section: Resultsmentioning

confidence: 99%

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Mishra

Hahn

Sadagopan

et al. 2021

Preprint

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Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced obesity and CMS in ovariectomized female and male mice. PDE9-I reduces abdominal, hepatic, and myocardial fat accumulation, stimulates mitochondrial activity in brown and white fat, and improves CMS, without altering activity or food intake. PDE9 localizes to mitochondria, and its inhibition stimulates lipolysis and mitochondrial respiration coupled to PPARa dependent gene regulation. PPARa upregulation is required for PDE9-I metabolic efficacy and is absent in non-ovariectomized females that also display no metabolic benefits from PDE9-I. The latter is compatible with estrogen receptor-a altering PPARa chromatin binding identified by ChIPSeq. In humans with heart failure and preserved ejection fraction, myocardial expression of PPARA and its regulated genes is reduced versus control. These findings support testing PDE9-I to treat obesity/CMS in men and postmenopausal women.

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Section: Resultsmentioning

confidence: 99%

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Mishra

Hahn

Sadagopan

et al. 2021

Preprint

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“…The most recognized mitophagy pathway in mammalian cells is dependent on Parkin 10 . A study revealed that Parkin-related mitophagy promotes cardiomyocyte death in IRI 11 . Another study has indicated that deficiency of autophagy aggravates tubular injury in proximal tubules and leads to damage of mitochondria in IRI-induced AKI model 12 .…”

Section: Introductionmentioning

confidence: 99%

c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway

Liu

Zheng

et al. 2021

Cell Death Dis

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Ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin–eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.

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“…Mitophagy is generally considered to play protective roles in the heart although excessive mitophagy can be detrimental under certain conditions (Song et al, 2015a;Nah et al, 2017). The protein levels of PINK1 and Parkin are decreased in the hearts of both type 1 and 2 diabetic animals (Xu et al, 2013;Tang et al, 2015;Shao et al, 2020), suggesting that mitophagy may be inhibited in the diabetic hearts. Using a novel dual fluorescent mitophagy reporter termed mt-Rosella, we labeled and traced mitochondrial fragments that are sequestered by the autophagosome and delivered to and degraded in the lysosome (Catanzaro et al, 2019;Kobayashi et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Fission and Mitophagy Coordinately Restrict High Glucose Toxicity in Cardiomyocytes

et al. 2020

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Hyperglycemia-induced mitochondrial dysfunction plays a key role in the pathogenesis of diabetic cardiomyopathy. Injured mitochondrial segments are separated by mitochondrial fission and eliminated by autophagic sequestration and subsequent degradation in the lysosome, a process termed mitophagy. However, it remains poorly understood how high glucose affects the activities of, and the relationship between, mitochondrial fission and mitophagy in cardiomyocytes. In this study, we determined the functional roles of mitochondrial fission and mitophagy in hyperglycemia-induced cardiomyocyte injury. High glucose (30 mM, HG) reduced mitochondrial connectivity and particle size and increased mitochondrial number in neonatal rat ventricular cardiomyocytes, suggesting an enhanced mitochondrial fragmentation. SiRNA knockdown of the pro-fission factor dynamin-related protein 1 (DRP1) restored mitochondrial size but did not affect HG toxicity, and Mdivi-1, a DRP1 inhibitor, even increased HG-induced cardiomyocyte injury, as shown by superoxide production, mitochondrial membrane potential and cell death. However, DRP1 overexpression triggered mitochondrial fragmentation and mitigated HG-induced cardiomyocyte injury, suggesting that the increased mitochondrial fission is beneficial, rather than detrimental, to cardiomyocytes cultured under HG conditions. This is in contrast to the prevailing hypothesis that mitochondrial fragmentation mediates or contributes to HG cardiotoxicity. Meanwhile, HG reduced mitophagy flux as determined by the difference in the levels of mitochondria-associated LC3-II or the numbers of mitophagy foci indicated by the novel dual fluorescent reporter mt-Rosella in the absence and presence of the lysosomal inhibitors. The ability of HG to induce mitochondrial fragmentation and inhibit mitophagy was reproduced in adult mouse cardiomyocytes. Overexpression of Parkin, a positive regulator of mitophagy, or treatment with CCCP, a mitochondrial uncoupler, induced mitophagy and attenuated HG-induced cardiomyocyte death, while Parkin knockdown had opposite effects, suggesting an essential role of mitophagy in cardiomyocyte survival under HG conditions. Strikingly, Parkin overexpression increased mitochondrial fragmentation, while DRP1 overexpression accelerated mitophagy flux, demonstrating a reciprocal activation loop that controls mitochondrial fission and mitophagy. Thus, strategies that promote the mutual positive interaction between mitochondrial fission and mitophagy while simultaneously maintain their levels within the physiological range would be expected to improve mitochondrial health, alleviating hyperglycemic cardiotoxicity.

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Increasing Fatty Acid Oxidation Prevents High-Fat Diet–Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy

Cited by 142 publications

References 55 publications

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway

Mitochondrial Fission and Mitophagy Coordinately Restrict High Glucose Toxicity in Cardiomyocytes

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