Mitochondrial complex II participates in normoxic and hypoxic regulation of α-keto acids in the murine heart

α-Keto acids (α-KAs) are not just metabolic intermediates but are also powerful modulators of different cellular pathways. Here, we tested the hypothesis that α-KA concentrations are regulated by complex II (succinate dehydrogenase = SDH), which represents an intersection between the mitochondrial respiratory chain for which an important function in cardiopulmonary oxygen sensing has been demonstrated, and the Krebs cycle, a central element of α-KA metabolism. SDH subunit D heterozygous (SDHD+/−) and wild-type (WT) mice were housed at normoxia or hypoxia (10% O2) for 4 days or 3 weeks, and right ventricular pressure, right ventricle/(left ventricle + septum) ratio, cardiomyocyte ultrastructure, pulmonary vascular remodelling, ventricular complex II subunit expression, SDH activity and α-KA concentrations were analysed. In both strains, hypoxia induced increases in right ventricular pressure and enhanced muscularization of distal pulmonary arteries. Right ventricular hypertrophy was less severe in SDHD+/− mice although the cardiomyocyte ultrastructure and mitochondrial morphometric parameters were unchanged. Protein amounts of SDHA, SDHB and SDHC, and SDH activity were distinctly reduced in SDHD+/− mice. In normoxic SDHD+/− mice, α-ketoisocaproate concentration was lowered to 50% as compared to WT animals. Right/left ventricular concentration differences and the hypoxia-induced decline in individual α-KAs were less pronounced in SDHD+/− animals indicating that mitochondrial complex II participates in the adjustment of cardiac α-KA concentrations both under normoxic and hypoxic conditions. These characteristics are not related to the hemodynamic consequences of hypoxia-induced pulmonary vascular remodelling, since its extent and right ventricular pressure were not affected in SDHD+/− mice albeit right ventricular hypertrophy was attenuated.

Research Highlights
► Right ventricular hypertrophy is less severe in SDHD+/− mice as compared to WT.
► Protein amounts of SDHA, SDHB and SDHC, and SDH activity are distinctly reduced in SDHD+/− mice.
► In normoxic SDHD+/− mice, α-ketoisocaproate concentration is lowered to 50% as compared to WT animals.
► Right/left ventricular differences and the hypoxic decline in individual α-KAs are less pronounced in SDHD+/− animals.
► Mitochondrial morphometric parameters are comparable in WT and SDHD+/− mice housed at normoxia or hypoxia.