Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Clinical Laboratory Medicine, The First Medical Centre, Medical School of Chinese People's Liberation Army, Beijing, China.
Clin Transl Med. 2024 Aug;14(8):e1806. doi: 10.1002/ctm2.1806.
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.
We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.
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 (Pgam5) 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 (Phb2) and phospho-defective (Phb2) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2 were resistant to alcohol-induced heart dysfunction.
We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2 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.
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.
诱导线粒体质量控制（MQC）机制对于应激期间重建线粒体稳态和细胞生物能学至关重要。虽然 MQC 的激活在各种心血管疾病中具有心脏保护作用，但在酒精性心肌病（ACM）中其确切作用和调节机制仍不完全清楚。
我们探讨了两种与线粒体相关的蛋白质，磷酸甘油酸变位酶 5（Pgam5）和抑制素 2（Phb2），在 ACM 期间是否影响雄性小鼠中的 MQC。
ACM 雄性小鼠模型中心肌 Pgam5 表达上调。值得注意的是，在 ACM 诱导后，雄性心肌细胞特异性 Pgam5 敲除（Pgam5）小鼠的心脏功能障碍明显逆转。同时，在酒精处理的雄性鼠源性新生心肌细胞中，Pgam5 耗竭可维持细胞存活并恢复线粒体动力学、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 与 Phb2 结合并诱导其 Ser91 去磷酸化。磷酸模拟（Phb2）和磷酸缺陷（Phb2）Phb2 突变体的替代转导分别减弱和增强了心肌细胞中与酒精相关的线粒体功能障碍。此外，表达 Phb2 的转基因雄性小鼠对酒精诱导的心脏功能障碍具有抗性。
我们得出结论，ACM 诱导的 Pgam5 上调导致 Pgam5 依赖性 Phb2 去磷酸化，导致心脏中的 MQC 不稳定和线粒体功能障碍。因此，调节 Pgam5/Phb2 相互作用可能为雄性 ACM 小鼠提供一种新的治疗策略。
