Institute of Mechanobiology and Medical Engineering, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
PKU-HKUST Shenzhen-Hong Kong Institution, Shenzhen 518000, China.
Int J Mol Sci. 2022 Oct 8;23(19):11934. doi: 10.3390/ijms231911934.
(1) Background: Heart failure with preserved ejection fraction (HFpEF) is a major subtype of HF with no effective treatments. Mitochondrial dysfunctions relevant to the imbalance of fusion and fission occur in HFpEF. Drp1 is a key protein regulating mitochondrial fission, and PINK1 is the upstream activator of Drp1, but their relationship with HF has not been clarified. The aim of the study is to investigate molecular mechanisms of mitochondrial dysfunctions in animals with hypertension-induced HFpEF. (2) Methods and Results: The hypertension-induced HFpEF model was established by feeding Dahl/SS rats with high salt, showing risk factors such as hypertension, mitochondrial dysfunctions, and so on. Physiological and biological measurements showed a decrease in the expression of mitochondrial function-related genes, ATP production, and mitochondrial fission index. PINK1 knockout in H9C2 cardiomyocytes showed similar effects. Moreover, PINK1 myocardium-specific overexpression activated Drp1 phosphorylation and enhanced mitochondrial fission to slow the progression of hypertension-induced HFpEF. (3) Conclusions: PINK1 could phosphorylate Drp1S616 to improve mitochondrial fission and relieve mitochondrial dysfunctions, which highlights potential treatments of HFpEF.
（1）背景：射血分数保留型心力衰竭（HFpEF）是心力衰竭的主要亚型，目前尚无有效的治疗方法。HFpEF 中存在与融合和裂变失衡相关的线粒体功能障碍。Drp1 是调节线粒体裂变的关键蛋白，而 PINK1 是 Drp1 的上游激活剂，但它们与心力衰竭的关系尚未阐明。本研究旨在探讨高血压诱导的 HFpEF 动物中线粒体功能障碍的分子机制。
（2）方法和结果：通过给 Dahl/SS 大鼠喂食高盐来建立高血压诱导的 HFpEF 模型，该模型表现出高血压、线粒体功能障碍等危险因素。生理和生物学测量显示，与线粒体功能相关的基因表达、ATP 产生和线粒体裂变指数降低。在 H9C2 心肌细胞中敲除 PINK1 也显示出类似的效果。此外，PINK1 心肌特异性过表达激活 Drp1 S616 的磷酸化，增强线粒体裂变，从而减缓高血压诱导的 HFpEF 的进展。
（3）结论：PINK1 可使 Drp1 S616 磷酸化，改善线粒体裂变，缓解线粒体功能障碍，这为 HFpEF 的潜在治疗提供了新的思路。
