MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States of America; Current address: Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France.
MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States of America.
Cell Calcium. 2022 Jul;105:102618. doi: 10.1016/j.ceca.2022.102618. Epub 2022 Jun 22.
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 Ca 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 Ca overload and the ensuing cell death induction. Notably, animal studies have already linked impaired mitochondrial Ca transport to the initiation/progression of HF. Mitochondrial Ca uptake is mediated by the Cauniporter (mtCU) that consists of the MCU pore under tight control by the Ca-sensing MICU1 and MICU2. The MICU1/MCU protein ratio has been validated as a predictor of the mitochondrial Ca 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.
心力衰竭（HF）是全球住院和死亡的主要原因。然而，由于用于研究的人体组织稀缺，并且从动物模型中获得的数据不能直接应用于人类，因此对于潜在分子机制的了解仍然有限。因此，对人体心脏标本的研究具有特别的意义。线粒体 Ca 处理是心力衰竭进展中的一个新兴主题，因为其调节对于心脏收缩的能量供应以及避免线粒体 Ca 过载和随之而来的细胞死亡诱导至关重要。值得注意的是，动物研究已经将受损的线粒体 Ca 转运与心力衰竭的起始/进展联系起来。线粒体 Ca 摄取由 Ca 载体（mtCU）介导，该载体由 MCU 孔在 Ca 感应的 MICU1 和 MICU2 的紧密控制下组成。MICU1/MCU 蛋白比已被验证为预测线粒体 Ca 摄取表型的指标。我们在这里首次确定了人心脏中线粒体 Ca 摄取体的蛋白组成。与非衰竭对照相比，两个调节蛋白 MICU1 和 MICU2 在衰竭的人心肌中升高，而 MCU 密度不变。此外，衰竭人心肌中的 MICU1/MCU 比值显著升高，表明 MICU1 和 MICU2 对 MCU 的门控发生改变。基于一小部分患者，心脏收缩功能（射血分数）的下降似乎与 MICU1/MCU 比值的增加相关。因此，我们的研究结果表明，mtCU 组成的适应性/失调变化可能在人类心力衰竭的起始/进展中起作用，并指向 MICU1 依赖性调节 mtCU 水平的潜在治疗靶点。
