Rationale: Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood.

Objective: To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication.

Methods and Results: Tfam inactivation by Nkx2.5^Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation.

Conclusions: Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

原理：尽管线粒体疾病通常会导致异常的心肌发育，但对线粒体影响心脏生长和功能的机制知之甚少。

目的：为了研究这些疾病的机制，我们研究了由Tfam（转录因子A，线粒体）失活引起的线粒体功能障碍的遗传模型.Tfam是线粒体基因转录和线粒体DNA复制所必需的核编码基因。

方法与结果： Nkx2.5 ^Cre失活Tfam导致线粒体功能障碍和胚胎致死性心肌发育不全。Tfam失活伴随着活性氧（ROS）产生增加和心肌细胞增殖减少。马赛克胚胎Tfam灭活证实心肌细胞增殖的阻滞是细胞自主的。RNA序列的转录谱分析证明了DNA损伤途径的激活。ROS的药理抑制作用或DNA损伤反应途径在培养的胎儿心肌细胞中恢复了心肌细胞的增殖。新生儿TfamAAV9-cTnT-Cre的失活导致进行性，致死性扩张型心肌病。值得注意的是，产后Tfam失活和线粒体功能破坏不会损害心肌细胞的成熟。相反，它增加了ROS的产生，激活了DNA损伤反应途径，并减少了心肌细胞的增殖。我们在出生后的第一个星期确定了一个短暂的窗口，这时对ROS的抑制或DNA损伤反应途径改善了Tfam失活的有害作用。

结论： Tfam失活引起的线粒体功能障碍引起ROS产生，激活DNA损伤反应，引起心肌细胞周期停滞，最终导致致命性心肌病。心肌细胞成熟不需要正常的线粒体功能。ROS或DNA损伤反应途径的药理抑制是预防由某种形式的线粒体功能障碍引起的心脏功能障碍的潜在策略。