Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation

Jian-rong Huang1, Ming-hua Zhang2, Ying-jie Chen1, Yu-ling Sun1, Zhi-min Gao1, Zhuo-jia Li1, Gui-ping Zhang1, Yuan Qin1, Xiao-yan Dai1, Xi-yong Yu1, Xiao-qian Wu1
1 The Fifth Affiliated Hospital & Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA KeyLaboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
2 Cardiovascular Department, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510180, China
Correspondence to: Xi-yong Yu:, Xiao-qian Wu:,
DOI: 10.1038/s41401-022-00919-1
Received: 26 January 2022
Accepted: 5 May 2022
Advance online: 2 June 2022


Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg−1·d−1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 μM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 μM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.
Keywords: obesity; metabolic cardiomyopathy; high fat diet; autophagy; mitophagy; mitochondrial dysfunction

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