Zaglia Tania, Campo Antonio, Moro Nicola, Di Mauro Vittoria, Borile Giulia, Menabò Roberta, Antonucci Salvatore, Poli Laura, Campesan Marika, Carullo Pierluigi, Martinazzi Sara, Luciani Giovanni B, Hammer Karin, Pesce Paola, Bariani Riccardo, Faggian Giuseppe, Maier Lars, Ventura Laura, De Stefani Diego, Mammucari Cristina, Rizzuto Rosario, Catalucci Daniele, Di Lisa Fabio, Mongillo Marco
Department of Biomedical Sciences, University of Padova, Padova 35131, Italy.
Veneto Institute of Molecular Medicine, Padova 35129, Italy.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2402639122. doi: 10.1073/pnas.2402639122. Epub 2025 Mar 11.
Regulation of mitochondrial Ca uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca uptake in cardiomyocytes entails "mitochondrion-to-cytoplasm" signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca/ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.
线粒体钙摄取的调节在心脏适应慢性应激源的过程中至关重要。钙处理异常，包括线粒体摄取机制异常，与病理性心脏肥大有关。有人提出增强线粒体钙单向转运体（MCU）的表达可干扰心力衰竭的不良适应性发展。在此，我们探讨了MCU调节是否会影响心脏对压力过载的反应。对处于心肌肥大不同阶段的人和小鼠心脏中的MCU含量进行了定量分析。在经过病毒辅助过表达或下调MCU的小鼠中，通过横向主动脉缩窄（TAC）分析心脏功能/结构。体外和离体实验确定了MCU调节对线粒体钙摄取、细胞表型和肥大信号传导的影响。在人和小鼠心脏中，MCU水平在心肌肥大的适应阶段升高，而在衰竭阶段下降。一致地，MCU的调节在心肌细胞/心脏适应慢性过载方面具有细胞自主效应。事实上，在TAC后，MCU下调加速了收缩功能障碍、间质纤维化和心力衰竭的发展。相反，MCU过表达延长了肥大反应的适应阶段，因为在TAC后的晚期阶段，心脏表现出保留的收缩力、无纤维化和完整的血管化。体外和离体分析表明，心肌细胞线粒体钙摄取的增强会引发“线粒体到细胞质”信号，导致ROS介导的Akt激活，这可能解释了对TAC心脏反应的保护作用。增强的线粒体钙摄取通过逆行线粒体 - 钙/ROS/Akt信号传导影响对压力过载的代偿反应，从而揭示了一种针对不良适应性心肌肥大的潜在可靶向机制。
