Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.

Autor:	Acin-Perez R; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Benincá C; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Fernandez Del Rio L; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Shu C; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Baghdasarian S; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Zanette V; Department of Bioinformatics, University Federal of Parana, Curitiba, Brazil., Gerle C; Institute for Protein Research, Osaka University, Suita, Japan.; RIKEN SPring-8 Center, Sayo-gun, Japan., Jiko C; Institute for Integrated Radiation and Nuclear Science, Kyoto University, Kyoto, Japan., Khairallah R; Myologica LLC., New Market, MD, USA., Khan S; Gencia Biotech, Charlottesville, VA, USA., Rincon Fernandez Pacheco D; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Shabane B; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Erion K; Epirium Bio Inc., San Diego, CA, USA., Masand R; Epirium Bio Inc., San Diego, CA, USA., Dugar S; Epirium Bio Inc., San Diego, CA, USA., Ghenoiu C; Epirium Bio Inc., San Diego, CA, USA., Schreiner G; Epirium Bio Inc., San Diego, CA, USA., Stiles L; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA., Liesa M; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA.; Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, USA.; Institut de Biologia Molecular de Barcelona, IBMB, CSIC, Barcelona, Catalonia, Spain., Shirihai OS; Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA.; Molecular Cellular Integrative Physiology, University of California, Los Angeles, CA, USA.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2023 May 15; Vol. 42 (10), pp. e111699. Date of Electronic Publication: 2023 Mar 13.
DOI:	10.15252/embj.2022111699
Abstrakt:	The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV. (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze:	MEDLINE
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