Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction

Mangyu Choe; Denis V Titov

doi:10.1101/2023.12.27.573435

Genetically encoded tool for manipulation of ΔΨm identifies the latter as the driver of integrative stress response induced by ATP Synthase dysfunction

bioRxiv [Preprint]. 2023 Dec 27:2023.12.27.573435. doi: 10.1101/2023.12.27.573435.

Authors

Mangyu Choe^{1

2}, Denis V Titov^{1

2

3}

Affiliations

¹ Department of Nutritional Sciences and Toxicology, University of California; Berkeley, CA 94720, USA.
² Department of Molecular and Cell Biology, University of California; Berkeley, CA 94720, USA.
³ Center for Computational Biology, University of California; Berkeley, CA 94720, USA.

Abstract

Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the Integrated Stress Response induced by ATP synthase inhibition in mammalian cells.

Publication types

Preprint

Grants and funding

DP2 GM132933/GM/NIGMS NIH HHS/United States