Abstract
Background: ATP-sensitive potassium channels (KATP), existing in both sarcolemmal and mitochondrial inner membranes, are thought to serve as metabolic sensors of the cell. In pathological hypertrophy, the heart requires increased workload to pump blood to meet the body’s needs. However, roles of KATP in hypertrophy stress signaling are not fully understood. Methods & Results: We aimed at investigating regulation of SUR2, the regulatory subunit of KATP, via a systems biology approach. We hypothesized that mitochondrial KATP mediates the protective response in hypertrophied hearts. A pressure-overload model by transverse aortic constriction (TAC) was employed to induce hypertrophy in SUR2 knockout (SUR2KO) males. These mice had enlarged left ventricles at baseline and developed further hypertrophy post TAC. Hypertrophied KO hearts exhibited significantly higher mortality, cardiac dysfunction, reduced mitochondrial DNA content and elevated ROS formation, which were associated with the altered SUR2 (mitoSUR2) variant expression. Among the mitoSUR2 variants, a 55-kDa mitoSUR2A variant was significantly up-regulated 4-fold in both TAC and SHAM treated KO hearts. We then analyzed whether the mitoSUR2 variants were associated with a key ROS regulator ShcP66 variant, ShcP52, using quantitative BRET assays. Our data showed that ShcP52 could directly bind to the mitoSUR2 variants. Our data indicates that these mitoSUR2 variants are involved in mediating ROS signaling. Comparative proteomic profiling and subsequent canonical pathway enrichment analyses revealed that mitochondrial function was the top affected system among the 41 identified pathways in SUR2KO hearts. Semi-quantitative comparisons between KO and WT data showed that the ETC activity was severely disturbed in SUR2KO-TAC mitochondria. Further data mining identified compromised cardiac parameters, affected molecular functions and possible diseases in hypertrophied SUR2KO hearts. Conclusions: Our novel findings reveal that altered mitochondrial SUR2-based KATP activities likely contribute to the hypertrophic phenotype and abnormal mitochondrial function in SUR2KO hearts, suggesting that these channels play an essential role in mitochondrial remodeling and energy sensing.
Published Version
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