A defect in mitochondrial protein translation influences mitonuclear communication in the heart

Feng Gao, Tian Liang, Yao Wei Lu, Xuyang Fu, Xiaoxuan Dong, Linbin Pu, Tingting Hong, Yuxia Zhou, Yu Zhang, Ning Liu, Feng Zhang, Jianming Liu, Andrea P. Malizia, Hong Yu, Wei Zhu, Douglas B. Cowan, Hong Chen, Xinyang Hu, John D. Mably, Jian’an Wang (), Da-Zhi Wang () and Jinghai Chen ()
Additional contact information
Feng Gao: Zhejiang University School of Medicine
Tian Liang: Zhejiang University School of Medicine
Yao Wei Lu: Harvard Medical School
Xuyang Fu: Zhejiang University School of Medicine
Xiaoxuan Dong: Zhejiang University School of Medicine
Linbin Pu: Zhejiang University School of Medicine
Tingting Hong: Zhejiang University School of Medicine
Yuxia Zhou: Zhejiang University School of Medicine
Yu Zhang: Zhejiang University School of Medicine
Ning Liu: Zhejiang University School of Medicine
Feng Zhang: Zhejiang University School of Medicine
Jianming Liu: Harvard Medical School
Andrea P. Malizia: Harvard Medical School
Hong Yu: Zhejiang University School of Medicine
Wei Zhu: Zhejiang University School of Medicine
Douglas B. Cowan: Harvard Medical School
Hong Chen: Harvard Medical School
Xinyang Hu: Zhejiang University School of Medicine
John D. Mably: University of South Florida Health Heart Institute, Morsani School of Medicine, University of South Florida
Jian’an Wang: Zhejiang University School of Medicine
Da-Zhi Wang: Harvard Medical School
Jinghai Chen: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.

Date: 2023
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DOI: 10.1038/s41467-023-37291-5

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