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

Author

Listed:
  • Feng Gao

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Tian Liang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Yao Wei Lu

    (Harvard Medical School
    Harvard Medical School)

  • Xuyang Fu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Xiaoxuan Dong

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Linbin Pu

    (Zhejiang University School of Medicine
    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
    Zhejiang University School of Medicine)

  • Feng Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Jianming Liu

    (Harvard Medical School
    Vertex pharmaceuticals, VCGT)

  • 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
    University of South Florida Health Heart Institute, Morsani School of Medicine, University of South Florida)

  • Jinghai Chen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

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.

Suggested Citation

  • 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 & Doug, 2023. "A defect in mitochondrial protein translation influences mitonuclear communication in the heart," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37291-5
    DOI: 10.1038/s41467-023-37291-5
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    References listed on IDEAS

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    1. Dan Shao & Outi Villet & Zhen Zhang & Sung Won Choi & Jie Yan & Julia Ritterhoff & Haiwei Gu & Danijel Djukovic & Danos Christodoulou & Stephen C. Kolwicz & Daniel Raftery & Rong Tian, 2018. "Glucose promotes cell growth by suppressing branched-chain amino acid degradation," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    2. Darwin Jeyaraj & Saptarsi M. Haldar & Xiaoping Wan & Mark D. McCauley & Jürgen A. Ripperger & Kun Hu & Yuan Lu & Betty L. Eapen & Nikunj Sharma & Eckhard Ficker & Michael J. Cutler & James Gulick & At, 2012. "Circadian rhythms govern cardiac repolarization and arrhythmogenesis," Nature, Nature, vol. 483(7387), pages 96-99, March.
    3. Riekelt H. Houtkooper & Laurent Mouchiroud & Dongryeol Ryu & Norman Moullan & Elena Katsyuba & Graham Knott & Robert W. Williams & Johan Auwerx, 2013. "Mitonuclear protein imbalance as a conserved longevity mechanism," Nature, Nature, vol. 497(7450), pages 451-457, May.
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