Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
Emory College of Arts and Sciences, Emory University, Atlanta, Georgia.
Am J Physiol Cell Physiol. 2021 Jun 1;320(6):C929-C942. doi: 10.1152/ajpcell.00508.2020. Epub 2021 Mar 24.
The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence that challenges this long-standing paradigm. Unexpectedly, conditional ablation in vivo in adult mouse cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function, despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting maintenance of respiratory chain assembly/function. Long-term inactivation, however, downregulated the core mtDNA transcription and replication machinery, leading to mitochondrial dysfunction and cardiomyopathy. Collectively, in contrast to the developing heart, these data reveal a striking resilience of the differentiated adult heart to acute insults to mtDNA regulation.
核基因组编码的线粒体 DNA（mtDNA）转录因子 A（TFAM）对于发育中和出生后的心脏中的线粒体能量产生是必不可少的；在成年心脏中推断出 TFAM 具有类似的作用。在这里，我们提供的证据挑战了这一长期存在的范例。出乎意料的是，在成年小鼠心肌细胞中进行体内条件性缺失导致了功能弹性的延长，其特征是 mtDNA 含量、线粒体功能和心脏功能保持不变，尽管存在线粒体结构改变和转录物丰度降低。值得注意的是，TFAM 蛋白水平并未直接决定成年心脏中的 mtDNA 含量，并且急性 TFAM 失活时保留了线粒体翻译，表明呼吸链组装/功能得到维持。然而，长期失活会下调核心 mtDNA 转录和复制机制，导致线粒体功能障碍和心肌病。总的来说，与发育中的心脏相比，这些数据揭示了分化的成年心脏对 mtDNA 调节的急性损伤具有惊人的弹性。
