Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 1, Pages 273-278Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1318547111
Keywords
energy metabolism; live-cell imaging
Categories
Funding
- Japan Society for the Promotion of Science
- Council for Science and Technology Policy
- Ministry of Health, Labor, and Welfare-Japan
- Ministry of Education, Culture, Sports, Science, and Technology-Japan
- Takeda Science Foundation
- Japan Heart Foundation
- Japan Cardiovascular Research Foundation
- Japan Intractable Diseases Research Foundation
- Japan Foundation of Applied Enzymology
- Japan Medical Association
- Uehara Memorial Foundation
- Mochida Memorial Foundation
- Banyu Foundation
- Naito Foundation
- Inoue Foundation for Science
- Osaka Medical Research foundation for Intractable Diseases
- Ichiro Kanehara Foundation
- Showa Houkoukai
- MRC [G1000461] Funding Source: UKRI
- Medical Research Council [G1000461] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [25860599, 24591096, 24790917, 23227006, 25461119, 25251016, 24657101, 25253047, 24570149, 24790757] Funding Source: KAKEN
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The oxidative phosphorylation (OXPHOS) system generates most of the ATP in respiring cells. ATP-depleting conditions, such as hypoxia, trigger responses that promote ATP production. However, how OXPHOS is regulated during hypoxia has yet to be elucidated. In this study, selective measurement of intramitochondrial ATP levels identified the hypoxia-inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS. A mitochondria-targeted, FRET-based ATP biosensor enabled us to assess OXPHOS activity in living cells. Mitochondria-targeted, FRET-based ATP biosensor and ATP production assay in a semi-intact cell system revealed that G0s2 increases mitochondrial ATP production. The expression of G0s2 was rapidly and transiently induced by hypoxic stimuli, and G0s2 interacts with OXPHOS complex V (FoF1-ATP synthase). Furthermore, physiological enhancement of G0s2 expression prevented cells from ATP depletion and induced a cellular tolerance for hypoxic stress. These results show that G0s2 positively regulates OXPHOS activity by interacting with FoF1-ATP synthase, which causes an increase in ATP production in response to hypoxic stress and protects cells from a critical energy crisis. These findings contribute to the understanding of a unique stress response to energy depletion. Additionally, this study shows the importance of assessing intramitochondrial ATP levels to evaluate OXPHOS activity in living cells.
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