Table1_How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?.DOCX

Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%–40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.

线粒体DNA（mitochondrial DNA）或线粒体相关核编码DNA的突变可引发多种多系统疾病，这类疾病统称为线粒体疾病（mitochondrial diseases）。每3例线粒体疾病患者中即有1例累及心肌，该病症被称为线粒体心肌病（mitochondrial cardiomyopathy, MCM），可伴发肥厚型、扩张型及致密化不全型心肌病。心脏作为高能量需求器官，线粒体占心肌细胞体积的30%~40%。线粒体功能障碍会引发能量耗竭，并对心脏功能产生不利影响。然而，线粒体与核DNA突变背景下的疾病发生与进展机制，目前仍未完全阐明。诱导多能干细胞（induced pluripotent stem cell, iPSC）衍生的心肌细胞（cardiomyocytes, CM）模型是研究线粒体心肌病的优质平台：因其与供体完全一致的遗传背景，可在体外培养体系中实现患者特异性目标表型的稳定重现。本文聚焦于利用患者特异性iPSC-CM开展的线粒体心肌病研究的最新进展，并进一步探讨iPSC-CM代谢成熟研究中的研究空白与技术突破——该方向对于线粒体功能障碍研究及新型治疗策略的开发均具有至关重要的意义。