背景:线粒体质量控制(MQC)机制的诱导对于应激期间线粒体稳态和细胞生物能的重建至关重要。尽管MQC激活在各种心血管疾病中具有心脏保护作用,其在酒精性心肌病(ACM)中的确切作用和调节机制尚不完全清楚.
方法:我们探索了两种线粒体相关蛋白,磷酸甘油酸变位酶5(Pgam5)和阻断素2(Phb2),影响ACM期间雄性小鼠的MQC。
结果:在ACM的雄性小鼠模型中,心肌Pgam5表达上调。值得注意的是,在ACM诱导之后,在雄性心肌细胞特异性Pgam5基因敲除(Pgam5cKO)小鼠中,心功能障碍明显逆转.同时,在酒精处理的雄性小鼠来源的新生心肌细胞中,Pgam5耗竭保留了细胞存活并恢复了线粒体动力学,线粒体自噬,线粒体生物发生和线粒体未折叠蛋白反应(mtUPR)。我们进一步发现,在酒精处理的心肌细胞中,Pgam5结合Phb2并诱导其在Ser91处的去磷酸化。磷酸化模拟物(Phb2S91D)和磷酸化缺陷(Phb2S9A)Phb2突变体的替代转导减弱和增强,分别,心肌细胞中与酒精相关的线粒体功能障碍。此外,表达Phb2S91D的转基因雄性小鼠对酒精诱导的心脏功能障碍具有抗性。
结论:我们得出结论,ACM诱导的Pgam5上调导致Pgam5依赖性Phb2S91去磷酸化,导致MQC不稳定和心脏线粒体功能障碍。因此,调节Pgam5/Phb2相互作用可能为雄性小鼠的ACM提供新的治疗策略。
结论:Pgam5基因敲除减轻酒精诱导的雄性小鼠心脏组织病理学和心功能障碍。Pgam5KO减少酒精诱导的心肌炎症,雄性小鼠的脂质过氧化和代谢功能障碍。Pgam5耗竭保护酒精暴露的雄性小鼠心肌细胞的线粒体功能。Pgam5耗尽使ACM中的MQC正常化。EtOH通过在Ser91处诱导Phb2去磷酸化而损害MQC。Pgam5与Phb2相互作用并诱导Phb2去磷酸化。表达Ser91磷酸模拟Phb2突变体的转基因小鼠对ACM具有抗性。
BACKGROUND: The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.
METHODS: We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.
RESULTS: Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction.
CONCLUSIONS: We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.
CONCLUSIONS: Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.