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

## TL;DR

The study shows that reducing the activity of the vacuolar-type H+-ATPase helps cells survive when mitochondria are not functioning properly.

## Contribution

The paper reveals a novel extra-organellar buffering mechanism involving v-ATPase inhibition to mitigate mitochondrial dysfunction.

## Key findings

- Partial v-ATPase loss modulates mitochondrial membrane potential and cristae structure.
- v-ATPase inhibition promotes cell fitness by altering pH and metabolic rewiring.
- The mechanism works in both cancer cells and mitochondrial disease patient models.

## Abstract

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.

Mitochondrial dysfunction underlies a multitude of human diseases. Here, the authors show that partial inhibition of the vacuolar-type H+-ATPase enhances cell fitness under mitochondrial stress.