Miro1-dependent mitochondria transfer from cardiomyocytes metabolically controls fibroblast fate to maintain heart homeostasis

Abstract Recent evidence indicates that mitochondria can move beyond their cell of origin and be internalized by neighboring cells, where they modulate cellular metabolism to influence cell fate. This process, termed intercellular mitochondria transfer, has recently been shown to contribute to tissue homeostasis across several organs. However, whether intercellular mitochondria transfer occurs in the heart and regulates its function remains unclear. Here, we identify intercellular mitochondria transfer from cardiomyocyte to cardiac fibroblasts as a critical regulator of heart homeostasis. Using complementary in vivo and in vitro approaches, we showed that cardiomyocytes transfer their mitochondria to cardiac fibroblasts through a Miro1-dependent mechanism and that this process prevents the profibrogenic activation of recipient fibroblasts under homeostatic conditions. Consistent with this finding, cardiomyocyte-specific Miro1 loss-of-function resulted in excessive cardiac fibrosis and impaired contractile function. Mechanistically, mitochondria transfer decreased succinate levels in recipient fibroblasts by enhancing SDHA expression and mitochondrial complex II activity, thereby inhibiting HIF1α-mediated profibrotic signaling. Finally, intravenous administration of isolated cardiomyocyte-derived mitochondria partially reversed fibroblast activation in mice with cardiomyocyte-specific Miro1 deficiency, further supporting the physiological relevance of mitochondria transfer. Taken together, our study reveals a novel mechanism by which cardiomyocytes maintain heart homeostasis and opens new therapeutic avenues for preventing cardiac fibrosis, a hallmark of cardiovascular diseases.