Abstract P3052: Dysregulation Of The Ampk-drp1 Axis Promotes Pathophysiological Remodeling Of Mitochondrial Ultrastructure And Ventricular Electrophysiological Function

• Published in: Circulation research Vol. 131; no. Suppl_1
• Main Authors: Rudokas, Michael W, Cacheux, Marine, Wu, Xiaohong, Young, Lawrence H, Akar, Fadi G
• Format: Journal Article
• Language: English
• Published: 05.08.2022
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3052

Abstract only AMP-activated protein kinase (AMPK), a master metabolic sensor, plays a central role in the regulation of mitochondrial (mito) function. AMPK activation inhibits mito fission potentially by modulating mito dynamics proteins, including dynamin-related protein 1 (DRP1). The role of the AMPK-DRP1 axis in electrophysiological (EP) function is unknown. Methods: We examined the impact of myocardial AMPK inactivation on mito ultrastructure by electron microscopy, mito dynamics proteins by western blot, and EP function by optical mapping in mice expressing an AMPK kinase dead isoform (AMPK-KD, N=3-7) vs littermate controls (Ctrl, N=3-6). Results: Quantification of mito morphology revealed increased mito area consistent with swelling (0.53 μm 2 vs 0.80 μm 2 , p<0.0001) and decreased mito count (0.68 mito/μm 2 vs 0.44 mito/μm 2 , p=0.13) in AMPK-KD vs Ctrl. Immunoblots revealed decreased DRP1 phosphorylation at S637 (a fission inhibiting site) with no major change in total DRP1, S616 phospho-DRP1, MFN1/2 or OPA1 levels in AMPK-KD. High resolution optical mapping of ex vivo perfused hearts uncovered marked (by 39.5%, p<0.001) conduction slowing ( Figure ) and a moderate increase in AP duration (43.8 ms vs 49.7 ms, p<0.05) reflecting widespread ventricular EP remodeling in AMPK-KD. Of note, discrete lines of functional conduction block were observed in 4/7 AMPK-KD but not Ctrl hearts consistent with pro-arrhythmic remodeling. Conclusions: Myocardial AMPK pathway inactivation causes mito ultrastructural abnormalities and pathological EP remodeling. The AMPK-DRP1 axis may be a novel target for arrhythmia suppression in metabolic disorders with defective AMPK downstream signaling.