Journal Article

Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart

Elezaby, Aly, Kraemer, Benjamin R., Haileselassie, Bereketeab, Glancy, Brian, Baena, Valentina, Syed, Zulfeqhar A., Larus, Isabel, Ferreira, Julio C. B., Lin, Amanda J., Ostberg, Nicolai P., Campos, Juliane C., Vijayan, Vijith, Bechara, Luiz R. G., Murphy, Elizabeth, Pokhrel, Suman, Mochly-Rosen, Daria, Sun, Junhui, Queliconi, Bruno B.

2024

Overview

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F F -ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury.

• Publisher: Nature Publishing Group
• Subject: Adenosine triphosphate / Adenosine Triphosphate - metabolism / Animals / Disease Models, Animal / Experiments / Flow cytometry / Heart / HEK293 Cells / Humans / Ischemia / Localization / Male / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria, Heart - metabolism / Mitochondrial Permeability Transition Pore - metabolism / Mitochondrial Proton-Translocating ATPases - metabolism / Myocardial Ischemia - metabolism / Myocardial Reperfusion Injury - metabolism / Myocardial Reperfusion Injury - pathology / Oxidative Stress - drug effects / Phosphorylation / Protein Binding / Proteins / Protons / Rats / Respiration / Troponin I - metabolism