PT  - JOURNAL ARTICLE
AU  - Yeyun Ouyang
AU  - Corey N. Cunningham
AU  - Jordan A. Berg
AU  - Ashish G. Toshniwal
AU  - Casey E. Hughes
AU  - Jonathan G. Van Vranken
AU  - Mi-Young Jeong
AU  - Ahmad A. Cluntun
AU  - Geanette Lam
AU  - Jacob M. Winter
AU  - Emel Akdoǧan
AU  - Katja K. Dove
AU  - Steven P. Gygi
AU  - Cory D Dunn
AU  - Dennis R Winge
AU  - Jared Rutter
TI  - Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms
AID  - 10.1101/2022.10.25.513802
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.25.513802
4099  - http://biorxiv.org/content/early/2022/10/27/2022.10.25.513802.short
4100  - http://biorxiv.org/content/early/2022/10/27/2022.10.25.513802.full
AB  - 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 the mitochondrial membrane potential is also 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 functions even with defective mitochondria.Competing Interest StatementThe authors have declared no competing interest.