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<p>Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects – besides a compendium of known mitochondrial translation quality control factors – is the loss of the vacuolar-type H<sup>+</sup>-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨ<sub>m</sub>) and cristae structure in both cancer cell lines and mitochondrial disease&#xa0;patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.</p>

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Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Geoffray Monteuuis,
  • Ryan Awadhpersad,
  • Daan van der Kolk,
  • Sachin K. Singh,
  • Tuula A. Nyman,
  • Alina Malyutina,
  • Nicola Zamboni,
  • Kari Moisio,
  • Juhana Juutila,
  • Ville Hietakangas,
  • Sara Seneca,
  • Christopher J. Carroll,
  • Christopher B. Jackson

摘要

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects – besides a compendium of known mitochondrial translation quality control factors – is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.