From the Department of Cardiology, Boston Children's Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan (Y.L.); Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil (S.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.).
Circ Res. 2018 Jan 5;122(1):74-87. doi: 10.1161/CIRCRESAHA.117.311349. Epub 2017 Oct 11.
Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood.
To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication.
inactivation by Nkx2.5 caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic 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 inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal 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 inactivation.
Mitochondrial dysfunction caused by 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.
尽管线粒体疾病常导致心肌发育异常，但线粒体影响心脏生长和功能的机制仍知之甚少。
为了研究这些疾病机制，我们研究了一种由 （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，该基因是线粒体基因转录和线粒体 DNA 复制所必需的核编码基因。
由 Nkx2.5 引起的 失活导致线粒体功能障碍和胚胎致死性心肌发育不全。 失活伴随着活性氧（ROS）的产生增加和心肌细胞增殖减少。通过 RNA-seq 进行的转录谱分析表明 DNA 损伤途径被激活。在培养的胎鼠心肌细胞中，ROS 或 DNA 损伤反应途径的药理学抑制恢复了心肌细胞的增殖。通过 AAV9-cTnT-Cre 进行的新生期 失活导致进行性、致死性扩张型心肌病。值得注意的是，出生后 失活和线粒体功能障碍不会损害心肌细胞的成熟。相反，它会增加 ROS 的产生，激活 DNA 损伤反应途径，并减少心肌细胞的增殖。我们发现，在出生后的第一周内存在一个短暂的窗口期，在此期间抑制 ROS 或 DNA 损伤反应途径可以改善 失活的不利影响。
由 失活引起的线粒体功能障碍导致 ROS 的产生增加，激活了 DNA 损伤反应，并导致心肌细胞细胞周期停滞，最终导致致命性心肌病。正常的线粒体功能对于心肌细胞的成熟不是必需的。抑制 ROS 或 DNA 损伤反应途径的药理学方法可能是预防某些形式的线粒体功能障碍引起的心脏功能障碍的一种潜在策略。
