Abstract 19529: FUNDC1 Deficiency Exacerbates Pathological Cardiac Remodeling and Contractile Dysfunction Through Suppression of DRP1

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Background: FUNDC1 (Fun14 domain containing protein 1) is a mitochondrial outer membrane protein to function in the recruitment of autophagic isolated membrane to mitochondria in hypoxic conditions. However, the role for FUNDC1 in heart failure remains unknown.

Methods: Wild type and FUNDC1 deficient mice were subjected to transverse aortic constriction (TAC) for 1 month. Echocardiography was employed to evaluate the heart function. Lectin-FITC (WGA) and Masson Trichrome staining were used to determine cardiac remodeling. Mitophagy was measure by TEM and Pink1-Parkin and Bnip3 were measured with Western Blot. Mitochondrial membrane potential was measured using JC-1 staining. ROS production was measured with DHE and mitoSOX. DRP1 and its S616 and S637 phosphorylation were evaluated using Western Blot. H9C2 myoblasts were employed for gain and loss of function for DRP1 using siRNA and adenovirus transfection.

Results: Chronic pressure overload triggered pathological cardiac remodeling (hypertrophy and interstitial fibrosis), contractile dysfunction (reduced ejection fraction and fraction shortening) and intracellular Ca2+ derangement, the effects of which were accentuated by FUNDC1 ablation. TAC procedure decreased mitochondrial membrane potential by 27.4% while increasing mitoSOX and DHE (28.5% and 35.0%). These responses were more pronounced in FUNDC1 knockout mice. Pressure overload elicited trivial effects on DRP1 levels and mitophagy although FUNDC1 deficiency drastically decreased DRP1 recruitment from cytosol to mitochondria and suppressed the mitochondrial fission. In vitro studies suggested that DRP1 transfection and silencing retarded and worsened, respectively, phenylephrine-induced (PE; 100 umol/L for 48 hours) cell hypertrophy.

Conclusion: These results demonstrate that FUNDC1 plays a pivotal role in the progress of heart failure. This study confirmed that FUNDC1 ablation exacerbates cardiac defects by a mechanism related to inhibition the recruitment of DRP1.

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