Mitochondria are one of the most important organelles in cardiomyocytes. Mitochondrial homeostasis is necessary for the maintenance of normal heart function. Mitochondria perform four major biological processes in cardiomyocytes: mitochondrial dynamics, metabolic regulation, Ca²⁺ handling, and redox generation. Additionally, the cardiovascular system is quite sensitive in responding to changes in mechanical stress from internal and external environments. Several mechanotransduction pathways are involved in regulating the physiological and pathophysiological status of cardiomyocytes. Typically, the extracellular matrix generates a stress-loading gradient, which can be sensed by sensors located in cellular membranes, including biophysical and biochemical sensors. In subsequent stages, stress stimulation would regulate the transcription of mitochondrial related genes through intracellular transduction pathways. Emerging evidence reveals that mechanotransduction pathways have greatly impacted the regulation of mitochondrial homeostasis. Excessive mechanical stress loading contributes to impairing mitochondrial function, leading to cardiac disorder. Therefore, the concept of restoring mitochondrial function by shutting down the excessive mechanotransduction pathways is a promising therapeutic strategy for cardiovascular diseases. Recently, viral and non-viral protocols have shown potentials in application of gene therapy. This review examines the biological process of mechanotransduction pathways in regulating mitochondrial function in response to mechanical stress during the development of cardiomyopathy and heart failure. We also summarize gene therapy delivery protocols to explore treatments based on mechanical stress–induced mitochondrial dysfunction, to provide new integrative insights into cardiovascular diseases.

线粒体是心肌细胞中最重要的细胞器之一。线粒体稳态对于维持正常心脏功能是必要的。线粒体在心肌细胞中执行四个主要的生物过程：线粒体动力学、代谢调节、Ca ²⁺处理和氧化还原生成。此外，心血管系统对内部和外部环境的机械应力变化的反应非常敏感。多种机械传导途径参与调节心肌细胞的生理和病理生理状态。通常，细胞外基质会产生应力加载梯度，该梯度可以被位于细胞膜中的传感器（包括生物物理和生化传感器）感测到。在随后的阶段，应激刺激将通过细胞内转导途径调节线粒体相关基因的转录。新的证据表明，力转导途径极大地影响了线粒体稳态的调节。过度的机械应力负荷会损害线粒体功能，导致心脏疾病。因此，通过关闭过度的力转导途径来恢复线粒体功能的概念是心血管疾病的一种有前途的治疗策略。最近，病毒和非病毒方案在基因治疗的应用中显示出了潜力。本综述探讨了心肌病和心力衰竭发展过程中机械应激调节线粒体功能的机械转导途径的生物学过程。 我们还总结了基因治疗递送方案，以探索基于机械应力诱导的线粒体功能障碍的治疗方法，从而为心血管疾病提供新的综合见解。