Mitochondrial protein coiled-coil-helix-coiled-coil-helix domain 10 (CHCHD10) as a novel contributor to heart failure through controlling microtubule organization

Abstract

Heart failure is a complex clinical syndrome that has high morbidity and mortality rates worldwide. Mitochondrial dysfunction is considered as the main pathogenesis of heart failure and has been extensively studied. Therapeutic strategies targeting mitochondrial dysfunction may be an effective treatment of heart failure. Increasing studies demonstrate the essential role of microtubule networks in regulating mitochondrial homeostasis and that disruption of microtubule networks under stress contributes to cardiac dysfunction by inducing mitochondrial dysfunction. Coiled-Coil-Helix-Coiled-coil-Helix Domain 10 (CHCHD10) is a mitochondrial protein and has been identified as a regulator of mitochondrial oxidative phosphorylation (OXPHOS). The majority of studies focus on neurodegenerative diseases and motor neuron diseases caused by CHCH10 variants. Recently, these CHCHD10 variants have been found to be associated with the development of cardiomyopathy while the specific role of CHCHD10 and the underlying mechanisms have not been fully explored. Therefore, this study aimed to investigate the role and underlying mechanisms of CHCHD10 in heart failure. First, cardiac CHCHD10 was significantly decreased in mice and patients with heart failure under obese, diabetic and inflammatory conditions. To this end, eight-week-old male cardiomyocyte-CHCHD10 deficient mice (CHCHD10F/F/Myh6-Cre) and their control littermates (CHCHD10F/F) were subjected to assessments of cardiac function using echocardiography. Cardiac CHCHD10-deficient mice showed severe heart failure which was accompanied by pathological alterations of cardiac metabolism and mitochondrial dysfunction, resulting from the disruption of mitochondrial homeostasis. Remodeling of microtubule networks, including remarkably increased expression of microtubule networks proteins, as well as disorganized microtubule networks was also observed in cardiac CHCHD10-deficient mice. Mechanistically, expression of CHCHD10 is reduced in response to metabolic stress which alters HIF-1α and p38/MAPK signaling pathways and causes microtubule disorganization. This eventually results in mitochondria dysfunction contributing to cardiac dysfunction in mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) under pathological conditions.

Key findings 1. Cardiac CHCHD10 was reduced in mice and patients with heart failure mediated by obesity, diabetes and inflammation. 2. Cardiac CHCHD10 deficiency induced severe heart failure in mice as indicated by systolic dysfunction, significantly induced ANP and BNP, and disarrayed arrangement of cardiomyocytes. 3. Cardiac CHCHD10 deletion triggered mitochondrial dysfunction and disrupted mitochondrial homeostasis, resulting from remodeling of microtubule networks, as evidenced by increased density of microtubule networks, and less organized microtubule networks. 4. By using cardiac CHCHD10-deficient mouse model and hiPSC-CMs model, the results showed that CHCHD10 deletion reduced the expression of HIF-1α which in turns elevated TUBB3 expression. On the other hand, CHCHD10 deletion mediated ROS and inflammatory cytokines production activate p38/MAPK signaling pathways, thereby increasing α/β-tubulin and MAP4 abundance. Taken together, these alterations jointly resulted in disorganized microtubule networks. 5. Overexpression of CHCHD10 in hiPSC-CMs elevated OXPHOS levels and ATP generation.

These findings suggest the cardioprotective role of CHCHD10 under physiological conditions. CHCHD10 regulates cardiac function via HIF-1α and p38/MAPK signaling pathways to modulate microtubule networks, thereby controlling mitochondrial homeostasis. This study provides us with new insights into a novel therapeutic target for the treatment of heart failure.

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