Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms
Abstract
Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
Data availability
The mass spectrometry data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD037405. RNA sequencing data have been deposited to the GEO Omnibus Repository with data set identifiers GSE151606, GSE212790, and GSE209726. Code for high-throughput dataset analysis is archived on GitHub at https://github.com/j-berg/ouyang_analysis_2022, and at Zenodo at https://doi.org/10.5281/zenodo.7212729.
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Sequencing of yeast mutants with or without phosphate depletionNCBI Gene Expression Omnibus, GSE212790.
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Sequencing of yeast mutantsNCBI Gene Expression Omnibus, GSE209726.
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MCT1 deletion in Saccharomyces cerevisiaeNCBI Gene Expression Omnibus, GSE151606.
Article and author information
Author details
Funding
National Institutes of Health (1F32GM140525)
- Corey N Cunningham
National Institutes of Health (1T32DK11096601)
- Jordan A Berg
National Institutes of Health (1F99CA253744)
- Jordan A Berg
National Institutes of Health (1F30CA243440-01A1)
- Jacob M Winter
National Institutes of Health (1K99HL168312-01)
- Ahmad A Cluntun
National Institutes of Health (R01GM110755)
- Dennis R Winge
National Institutes of Health (R35GM131854)
- Jared Rutter
Damon Runyon Cancer Research Foundation (DRG-2359-19)
- Jonathan G Van Vranken
Howard Hughes Medical Institute
- Jared Rutter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Ouyang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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