Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria‐Associated ER Membrane

作者：Miao Yu, Min Song, Manna Zhang, Shuangshuang Chen, Baoqiang Ni, Xuechun Li, Wei Lei, Zhenya Shen, Yong Fan, Jianyi Zhang, Shijun Hu · 发表于：Cell Proliferation · 年份：2025 · DOI：10.1111/cpr.70002 · 被引用次数：8 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、RNA and protein synthesis mechanisms

ABSTRACT m.3243A>G is the most common pathogenic mtDNA mutation. High energy‐demanding organs, such as heart, are usually involved in mitochondria diseases. However, whether and how m.3243A>G affects cardiomyocytes remain unknown. We have established patient‐specific iPSCs carrying m.3243A>G and induced cardiac differentiation. Cardiomyocytes with high m.3243A>G burden exhibited hypertrophic phenotype. This point mutation is localised in MT‐TL1 encoding tRNA Leu (UUR) . m.3243A>G altered tRNA Leu (UUR) conformation and decreased its stability. mtDNA is essential for mitochondrial function. Mitochondria dysfunction occurred and tended to become round. Its interaction with ER, mitochondria‐associated ER membrane (MAM), was disrupted with decreased contact number and length. MAM is a central hub for calcium trafficking. Disrupted MAM disturbed calcium homeostasis, which may be the direct and leading cause of cardiomyocyte hypertrophy, as MAM enforcement reversed this pathological state. Considering the threshold effect of mitochondrial disease, mito‐TALENs were introduced to eliminate mutant mitochondria and release mutation load. Mutation reduction partially reversed the cellular behaviour and made it approach to that of control one. These findings reveal the pathogenesis underlying m.3243A>G from perspective of organelle interaction, rather than organelle. Beyond mitochondria quality control, its proper interaction with other organelles, such as ER, matters f...