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Mitonuclear protein imbalance as a conserved longevity mechanism

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  • Riekelt H. Houtkooper

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
    Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands)

  • Laurent Mouchiroud

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

  • Dongryeol Ryu

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

  • Norman Moullan

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

  • Elena Katsyuba

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

  • Graham Knott

    (BioEM Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

  • Robert W. Williams

    (Department of Anatomy and Neurobiology and Center for Integrative and Translational Genomics)

  • Johan Auwerx

    (Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland)

Abstract

Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:497:y:2013:i:7450:d:10.1038_nature12188
    DOI: 10.1038/nature12188
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    Cited by:

    1. Zihao Wang & Qian Zhang & Yayun Jiang & Jun Zhou & Ye Tian, 2024. "ASI-RIM neuronal axis regulates systemic mitochondrial stress response via TGF-β signaling cascade," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Tang Cam Phung Pham & Steffen Henning Raun & Essi Havula & Carlos Henriquez-Olguín & Diana Rubalcava-Gracia & Emma Frank & Andreas Mæchel Fritzen & Paulo R. Jannig & Nicoline Resen Andersen & Rikke Kr, 2024. "The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Kejun Ying & José P. Castro & Anastasia V. Shindyapina & Alexander Tyshkovskiy & Mahdi Moqri & Ludger J. E. Goeminne & Sofiya Milman & Zhengdong D. Zhang & Nir Barzilai & Vadim N. Gladyshev, 2024. "Depletion of loss-of-function germline mutations in centenarians reveals longevity genes," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Liang Yang & Zifeng Ruan & Xiaobing Lin & Hao Wang & Yanmin Xin & Haite Tang & Zhijuan Hu & Yunhao Zhou & Yi Wu & Junwei Wang & Dajiang Qin & Gang Lu & Kerry M. Loomes & Wai-Yee Chan & Xingguo Liu, 2024. "NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Eirini Lionaki & Ilias Gkikas & Ioanna Daskalaki & Maria-Konstantina Ioannidi & Maria I. Klapa & Nektarios Tavernarakis, 2022. "Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Gabriela Poliacikova & Marine Barthez & Thomas Rival & Aïcha Aouane & Nuno Miguel Luis & Fabrice Richard & Fabrice Daian & Nicolas Brouilly & Frank Schnorrer & Corinne Maurel-Zaffran & Yacine Graba & , 2023. "M1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    7. 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.

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