Qaqorh Tasneem, Takahashi Yusuke, Sameshima Kohei, Otani Kentaro, Yazawa Issei, Nishida Yuya, Tonai Kohei, Fujihara Yoshitaka, Honda Mizuki, Oki Shinya, Ohkawa Yasuyuki, Thorburn David R, Frazier Ann E, Takeda Atsuhito, Ikeda Yoshihiko, Sakaguchi Heima, Watanabe Takuya, Fukushima Norihide, Tsukamoto Yasumasa, Makita Naomasa, Yamaguchi Osamu, Murayama Kei, Ohtake Akira, Okazaki Yasushi, Kimura Takanari, Kato Hisakazu, Inoue Hijiri, Matsuoka Ken, Takashima Seiji, Shintani Yasunori
Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
Sci Adv. 2025 Apr 4;11(14):eadq1575. doi: 10.1126/sciadv.adq1575.
Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, . Genetic ablation of in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.
氧化磷酸化缺陷导致目前难以治疗的线粒体疾病（MD），心脏受累显著影响预后。代谢缺陷后从代偿到功能障碍转变的潜在机制仍不清楚。在此，我们对一名线粒体心肌病（MCM）患者的心脏进行了空间分辨转录组学和单核RNA测序（snRNA-seq），并结合了心脏特异性Ndufs6基因敲低（FS6KD）的MCM小鼠模型。心肌细胞在代谢扰动引起的细胞类型中表现出最具异质性的表达图谱，伪时间轨迹分析揭示了从代偿到严重受损的动态细胞状态转变。这一进展与一种转录因子的短暂上调相吻合。在FS6KD中对该转录因子进行基因敲除证实了其关键作用，以雌性特异性方式有效延缓了心肌病进展。我们的研究结果突出了该转录因子在女性MCM进展中的命运决定作用，并且最新的转录组分析将有助于阐明MD进展的潜在机制。
