C1qbp, a Novel Cyclophilin‐D Interacting Protein, Regulates Mitochondrial Permeability Transition and Injury In The Heart

Abstract

The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. However, so far the only confirmed component of the pore is Cyclophilin D (CypD). Our laboratory has previously identified Complement 1q‐binding protein (C1qbp) as a novel CypD‐interacting molecule and a negative regulator of MPT‐dependent cell death. C1qbp is an acidic homotrimer with proposed roles in inflammation, cancer progression, biogenesis of respiratory chain components, and overall mitochondrial ultrastructure. However, its effects in the cardiac system remain untested. We therefore hypothesized that “activation” of C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against necrotic death. We first identified several putative C1qbp ligands using an in silico screen. Treatment of cultured cardiac myocytes with these ligands dose‐dependently protected the cells against oxidative stress‐induced necrosis. To investigate the effects of C1qbp in the myocardium we generated gain‐ and loss‐of‐function mice. Transgenic C1qbp overexpression resulted in decreased mitochondrial respiration and decreased ATP synthase activity, although to our surprise MPT remained unchanged. Interestingly, C1qbp+/− mice also exhibited decreased basal mitochondrial respiration but in this case MPT was sensitized. Neither overexpression nor depletion of C1qbp significantly affected baseline heart function at 3 months of age. When subjected to myocardial infarction, infarct size was unaffected in the C1qbp transgenic mice, consistent with the lack of an effect on MPT. In contrast infarct size was increased in the C1qbp deficient mice, in line with the sensitization of cardiac mitochondria from these mice to MPT Taken together, our results suggest that C1qbp is required for normal regulation of the MPT pore, mitochondrial function, and sensitivity to injury in the heart.Support or Funding InformationNIH HL094404This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.