Cell Signal. 2024 Oct 22. pii: S0898-6568(24)00457-1. [Epub ahead of print] 111482
Xiaomeng Zhang,
Xiaoqian Chang,
Jingyu Deng,
Congye Li,
Yuan Li,
Yangzhi Zheng,
Rongjin Yang,
Xiaoming Xu,
Wenjun Yan,
Fuyang Zhang,
Yunlong Xia,
Huishou Zhao,
Pingping Xing,
Guigao Guo,
Fengyue Ding,
Ling Tao,
Shan Wang.
Mammalian mitochondrial DNA (mtDNA) encodes a total of 13 proteins, all of which are subunits of enzyme complexes of the oxidative phosphorylation. The mtDNA-encoded protein synthesis depends on the mitochondrial ribosomal proteins (MRPs), which assemble to form a specialized form of ribosome. Some mtDNA-encoded proteins have been reported to be reduced after myocardial ischemic injury. However, the molecular mechanisms responsible for this decrease and whether this decrease is involved in myocardial ischemia/reperfusion (I/R) injury remains unknown. Here, we found that the mtDNA-encoded protein levels were significantly decreased after I/R injury, while the mRNA levels of these genes were either increased or had no significant change. Subsequently, by querying and analyzing public database resources, we found that the expression of many mitochondrial translation-related proteins tended to decrease after myocardial infarction injury, and the reduction in the expression of these proteins was most obvious for Mrpl42. Furthermore, we found that cardiac Mrpl42 knockdown aggravated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, while restoring Mrpl42 expression in the heart reduced I/R injury. Mrpl42 knockdown impaired the translation of mtDNA-encoded genes, ultimately led to aberrations in mitochondrial morphology and respiratory function. In addition, we found that the decrease in the expression of Mrpl42 after I/R injury was caused by the downregulation of Nrf2, which directly regulates Mrpl42 transcription. Our study revealed that ischemic downregulation of Mrpl42 expression and subsequent inhibition of mitochondrial translation contribute to cardiac I/R injury. Targeting Mrpl42 may be a novel therapeutic intervention for cardiac I/R injury and myocardial infarction.
Keywords: Mitochondria encoded gene; Mitochondria translation; Mrpl42; Myocardial ischemia/reperfusion injury