Abstract 19194: FUNDC1 Regulates Mitochondrial Dynamics to Participate in High Fat Diet-Induced Cardiomyopathy
Introduction: The outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, although its role in high fat diet intake-induced myopathic changes remains poorly understood. High fat diet intake triggers cardiac geometric and functional anomalies. Given the key role of mitophagy in the maintenance of mitochondrial homeostasis, this study was designed to evaluate the role of FUNDC1 in the regulation of mitophagy and cardiac homeostasis in the face of high fat diet intake.
Methods: Wild type (WT) and FUNDC1 mutant (FUNDC1-/-) mice were fed low fat diet (LFD) or high fat diet (HFD) for 20 weeks. Metabolic rate, glucose tolerance, Echocardiography, cardiomyocyte mechanical function, aconitase activity, ROS generation and mitochondrial respiration were assessed. Cell signaling pathways were evaluated using Western blot analysis.
Results: FUNDC1 ablation did not affect HFD-induced adiposity and insulin resistance, as evidenced by body weight gain and glucose intolerance. In addition, there was little difference in metabolic parameters (VO2, VCO2, RER, energy expenditure and physical activity) between WT and FUNDC1-/- mice fed HFD. However, FUNDC1 ablation accentuated HFD-elicited cardiac contractile dysfunction, as evidenced by echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties. HFD-feeding caused more extensive mitochondrial injury and ROS generation with a more pronounced effect in FUNDC1-/- mice. Myocardial autophagy was drastically reduced with a much more pronounced effect in FundC1 deficient mice. Mitochondrial respiration from HFD-FUNDC1-/- mice was reduced during ADP-dependent respiration compared with WT mice. HFD down-regulated phosphorylation of FUNDC1, promoted the dissociation of FUNDC1 from both OPA1 and LC3B while facilitating the association with DNM1L/DRP1, denoting inhibited mitochondrial fission and mitophagy. Furthermore, the effect of HFD on interaction of OPA1, DNM1L/DRP1 and LC3B was exacerbated by FUNDC1 deletion.
Conclusions: Our work revealed that FUNDC1 ablation exacerbates HFD-induced cardiac dysfunction and mitochondrial injury, possibly in association with inhibition of appropriate mitochondrial fission and thus cardiac autophagy.
Author Disclosures: N. Hu: None. S. Wang: None. Y. Zhang: None. J. Ren: None.
- © 2016 by American Heart Association, Inc.