FUNDC1 is Essential for Maintaining Cardiac Function During Prolonged Fasting

Abstract

Mitochondrial quality control via mitophagy is necessary to ensure proper metabolic functioning. However, various heart diseases have been associated with mitochondrial dysfunction and thus linked to increased mortality. Our past studies have shown a time-dependent differential effect of fasting on cardiac mitophagy. Specifically, one-day fasting accelerated mitophagy flux in the mouse heart, whereas two-day fasting actually reduced mitophagy flux, which was associated with the impairment of cardiac function. However, it remains unclear if the reduced mitophagy was responsible for the impaired cardiac function. In the present study, we determined the functional role of mitophagy in the heart during fasting using mice lacking FUNDC1, a mitochondrial outer-membrane protein that serves as a mitophagy receptor. We demonstrated that a two-day fasting impaired cardiac function in wild-type mice, which was exacerbated in FUNDC1 knockout (KO) mice as determined by echocardiography and hemodynamic measurements. This suggests that FUNDC1 or FUNDC1-mediated mitophagy was essential for maintaining cardiac function during fasting. Additionally, the total ATP levels in the hearts showed no dramatic difference between fasted wild type mice and FUNDC1 KO mice, suggesting that the exacerbated cardiac function in FUNDC1 KO mice was likely unrelated to ATP production. Interestingly, FUNDC1 deficiency reduced the expression of cardiac alpha myosin heavy chain (α-MHC) but increased that of β-MHC, a gene that normally expresses during fetal development stage and has the lowest contractile capability among the 3 MHC isoforms. Thus, the altered expression of α-MHC and β-MHC might have contributed to the more severe cardiac dysfunction in FUNDC1 KO mice during fasting.