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

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 o...

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Published in:The EMBO journal Vol. 42; no. 10; pp. e111699 - n/a
Main Authors: Acin‐Perez, Rebeca, Benincá, Cristiane, Fernandez del Rio, Lucia, Shu, Cynthia, Baghdasarian, Siyouneh, Zanette, Vanessa, Gerle, Christoph, Jiko, Chimari, Khairallah, Ramzi, Khan, Shaharyar, Rincon Fernandez Pacheco, David, Shabane, Byourak, Erion, Karel, Masand, Ruchi, Dugar, Sundeep, Ghenoiu, Cristina, Schreiner, George, Stiles, Linsey, Liesa, Marc, Shirihai, Orian S
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 15.05.2023
Springer Nature B.V
John Wiley and Sons Inc
Subjects:
Adenosine triphosphate
Adenosine Triphosphate - metabolism
Animals
ATP
ATP hydrolysis
ATP synthase
ATPase Inhibitor (ATPIF1)
Complex V
Duchenne's muscular dystrophy
Dystrophy
Electron transport
EMBO21
EMBO24
Energy balance
Epicatechin
Homeostasis
Hydrolysis
Life Sciences
Mice
Mitochondria
Mitochondria - metabolism
Muscle strength
Muscular dystrophy
Proteins - metabolism
Proton-Translocating ATPases - metabolism
Protonmotive force
Respiration
Respiratory function
Synthesis
epicatechin
muscular dystrophy
ATPase Inhibitor (ATPIF1)
ATP hydrolysis
Complex V
ISSN:0261-4189, 1460-2075, 1460-2075
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Summary: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. Synopsis In mitochondria, Complex V can rotate forward or reverse to either synthesize or hydrolyze ATP respectively. Here, isolated inhibition of the reverse activity of CV is sufficient to prevent ATP depletion in conditions of impaired respiration. A new assay to quantify ATP hydrolysis by ATP synthase (CV) shows that CV reverse activity occurs in coupled mitochondria. The polyphenol (+)‐Epicatechin is identified as a selective inhibitor of CV reverse activity while leaving synthesis unaffected. In cells with impaired respiratory function (+)-Epicatechin can increase cellular ATP content without restoring respiratory function. Muscle injury in a mouse model of Duchenne Muscular Dystrophy results in an increased CV reverse activity that correlates with the loss of muscle strength. (+)‐Epicatechin decreases ATP hydrolysis and improves muscle force in the Duchenne Muscular Dystrophy mouse model. Graphical Abstract Reverse activity of ATP synthase occurs in healthy mitochondria and is increased with respiratory chain dysfunction. Inhibition of ATP hydrolysis, alone, is sufficient to prevent ATP depletion, restore cellular function and improve muscle strength in model of Duchenne Muscular Dystrophy.
Bibliography:May 2023
These authors contributed equally to this work
et al
See also
GE Valdebenito
ObjectType-Article-1
SourceType-Scholarly Journals-1
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See also: GE Valdebenito et al (May 2023)
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.15252/embj.2022111699