Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (RNA-seq)

Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that inhibition of mCa2+ uptake in fibroblasts enhances myofibroblast formation and this translates to increased fibrosis following injury. Fibrotic signaling alters the gating of the mitochondrial calcium uniporter (mtCU) to reduce mCa2+ uptake and induce specific changes in metabolism. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent demethylases which epigenetically modify promoter regions specific to the myofibroblast gene program resulting in differentiation. Our results uncover an important role for mCa2+ uptake beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.

成纤维细胞（fibroblast）向肌成纤维细胞（myofibroblast）的分化在初始愈合应答中发挥关键作用，但过度的肌成纤维细胞活化会引发病理性纤维化。因此，阐明肌成纤维细胞形成的潜在机制至关重要。本研究发现，线粒体钙（mitochondrial calcium, mCa²+）信号通路是调控肌成纤维细胞分化与纤维化的关键机制。研究证实，抑制成纤维细胞的mCa²+摄取会促进肌成纤维细胞形成，这一效应在损伤后表现为纤维化程度加剧。纤维化相关信号通路会改变线粒体钙单向转运体（mitochondrial calcium uniporter, mtCU）的门控特性，从而降低mCa²+摄取并诱导代谢发生特异性改变。依赖mCa²+的代谢重编程会激活α-酮戊二酸（α-ketoglutarate, αKG）依赖型去甲基化酶，后者通过表观遗传修饰肌成纤维细胞基因程序特异性启动子区域，最终促成细胞分化。本研究结果揭示了mCa²+摄取在代谢调控与细胞死亡之外的重要功能，并证实mCa²+信号通路可通过调控表观基因组来影响细胞分化。