LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.
LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.
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LONP1 介导的线粒体质量控制可保障心脏发育中的代谢变化。
DOI：
10.1242/dev.200458
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发表时间：
2022-03
期刊：
影响因子：
4.6
通讯作者：
Yang Zhongzhou
中科院分区：
文献类型：
--
作者：
Zhao Ke;Huang Xinyi;Zhao Wukui;Lu Bin;Yang Zhongzhou
线粒体基质AAA+Lon蛋白酶（LONP1）降解错误折叠或未组装的蛋白质，这在线粒体质量控制中起着关键作用。在心脏发育过程中，代谢从无氧糖酵解转变为线粒体氧化磷酸化（此处句子不完整，最后一个单词“pho”可能是“phosphorylation”的缩写，即“磷酸化”）。
The mitochondrial matrix AAA+ Lon protease (LONP1) degrades misfolded or unassembled proteins, which play a pivotal role in mitochondrial quality control. During heart development, a metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation takes place, and this process relies highly on functional mitochondria. However, the relationship between mitochondrial quality control machinery and metabolic shifts is elusive. Here, we interfered with mitochondrial quality control by inactivating Lonp1 in embryonic cardiac tissue and found severely impaired heart development, leading to embryonic lethality. Mitochondrial swelling, cristae loss and abnormal protein aggregates were evident in the mitochondria of Lonp1-deficient cardiomyocytes. Accordingly, the p-eIF2α-ATF4 pathway was triggered, and nuclear translocation of ATF4 was observed. We further demonstrated that ATF4 negatively regulates the expression of Tfam while promoting that of Glut1, which was responsible for the disruption of the metabolic shift to oxidative phosphorylation. Meanwhile, elevated levels of reactive oxygen species were observed in Lonp1 mutant cardiomyocytes. This study revealed that LONP1 safeguards metabolic shifts in the developing heart by controlling mitochondrial protein quality and implies that disrupted mitochondrial quality control may cause prenatal cardiomyopathy.