INSERM U1048 I2MC, Toulouse, Cedex 4, France.
Université Paul Sabatier, Toulouse, France.
EMBO Mol Med. 2017 Jun;9(6):770-785. doi: 10.15252/emmm.201607096.
PIKfyve is an evolutionarily conserved lipid kinase that regulates pleiotropic cellular functions. Here, we identify PIKfyve as a key regulator of cardiometabolic status and mitochondrial integrity in chronic diet-induced obesity. , we show that PIKfyve is critical for the control of mitochondrial fragmentation and hypertrophic and apoptotic responses to stress. We also provide evidence that inactivation of PIKfyve by the selective inhibitor STA suppresses excessive mitochondrial ROS production and apoptosis through a SIRT3-dependent pathway in cardiomyoblasts. In addition, we report that chronic STA treatment improves cardiometabolic profile in a mouse model of cardiomyopathy linked to obesity. We provide evidence that PIKfyve inhibition reverses obesity-induced cardiac mitochondrial damage and apoptosis by activating SIRT3. Furthermore, treatment of obese mice with STA improves left ventricular function and attenuates cardiac hypertrophy. In contrast, STA is not able to reduce isoproterenol-induced cardiac hypertrophy in SIRT3.KO mice. Altogether, these results unravel a novel role for PIKfyve in obesity-associated cardiomyopathy and provide a promising therapeutic strategy to combat cardiometabolic complications in obesity.
PIKfyve 是一种进化上保守的脂质激酶，调节多种细胞功能。在这里，我们确定 PIKfyve 是慢性饮食诱导肥胖症中心脏代谢状态和线粒体完整性的关键调节剂。我们表明，PIKfyve 对于控制线粒体片段化以及对压力的肥大和凋亡反应至关重要。我们还提供证据表明，选择性抑制剂 STA 通过 SIRT3 依赖性途径失活 PIKfyve，可抑制心肌细胞中超氧自由基的产生和凋亡。此外，我们报告称，慢性 STA 治疗可改善与肥胖相关的心肌病小鼠模型中的心脏代谢特征。我们提供的证据表明，PIKfyve 抑制通过激活 SIRT3 逆转肥胖引起的心脏线粒体损伤和凋亡。此外，STA 治疗可改善肥胖小鼠的左心室功能并减弱心脏肥大。相比之下，STA 不能减少 SIRT3.KO 小鼠中异丙肾上腺素诱导的心脏肥大。总而言之，这些结果揭示了 PIKfyve 在肥胖相关心肌病中的新作用，并为肥胖相关代谢并发症提供了一种有前途的治疗策略。
