Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart

Advancements in cross-linking mass spectrometry bridge the gap between purified systems and native tissue environments, allowing the detection of protein structural interactions in their native state. In this study, we used isobaric quantitative protein interaction reporter (iqPIR) technology to compare the mitochondrial protein interactomes in healthy and failing murine hearts 4 weeks after transverse aortic constriction. The failing heart interactome includes 588 statistically significant cross-linked peptide pairs altered in the disease condition. We observed an increase in the assembly of ketone oxidation oligomers corresponding to an increase in ketone metabolic utilization; remodeling of NDUA4 interaction in Complex IV, likely contributing to impaired mitochondrial respiration; and conformational enrichment of the ADP/ATP carrier ADT1, which is non-functional for ADP/ATP translocation but likely possesses non-selective conductivity. Our application of quantitative cross-linking technology in cardiac tissue provides molecular-level insights into the complex mitochondrial remodeling in heart failure while bringing forth new hypotheses for pathological mechanisms. Caudal, Tang, et al. use isobaric quantitative protein interaction reporter (iqPIR) technology to compare the mitochondrial protein interactome in healthy and failing murine hearts, providing molecular-level insights into complex mitochondrial remodeling in heart failure.