Altered composition of the mitochondrial Ca2+uniporter in the failing human heart

Heart failure (HF) is a leading cause of hospitalization and mortality worldwide. Yet, there is still limited knowledge on the underlying molecular mechanisms, because human tissue for research is scarce, and data obtained in animal models is not directly applicable to humans. Thus, studies of human heart specimen are of particular relevance. Mitochondrial Ca2+ handling is an emerging topic in HF progression because its regulation is central to the energy supply of the heart contractions as well as to avoiding mitochondrial Ca2+ overload and the ensuing cell death induction. Notably, animal studies have already linked impaired mitochondrial Ca2+ transport to the initiation/progression of HF. Mitochondrial Ca2+ uptake is mediated by the Ca(2+)uniporter (mtCU) that consists of the MCU pore under tight control by the Ca2+-sensing MICU1 and MICU2. The MICU1/ MCU protein ratio has been validated as a predictor of the mitochondrial Ca(2+)uptake phenotype. We here determined for the first time the protein composition of the mtCU in the human heart. The two regulators MICU1 and MICU2, were elevated in the failing human heart versus non-failing controls, while the MCU density was unchanged. Furthermore, the MICU1/MCU ratio was significantly elevated in the failing human hearts, suggesting altered gating of the MCU by MICU1 and MICU2. Based on a small cohort of patients, the decrease in the cardiac contractile function (ejection fraction) seems to correlate with the increase in MICU1/ MCU ratio. Our findings therefore indicate a possible role for adaptive/maladaptive changes in the mtCU composition in the initiation/progression of human HF in humans and point to a potential therapeutic target at the level of the MICU1-dependent regulation of the mtCU.

Automated summary

Heart failure is a significant cause of hospitalization and mortality worldwide. The regulation of mitochondrial calcium handling appears to play a crucial role in the progression of heart failure. This study investigated the protein composition of mitochondrial calcium uniporter (mtCU) in human hearts and observed alterations in the regulators MICU1 and MICU2, suggesting a possible role for adaptive/maladaptive changes in mtCU composition in the initiation/progression of human heart failure.