Mitochonic Acid 5 Improves Mitochondrial Respiration Following Alcohol-Induced Mitochondrial Dysfunction

Abstract

Chronic alcohol exposure can lead to the development of Alcohol Induced Cardiomyopathy (ACM). The pathological changes in ACM have been suggested to be largely caused by mitochondrial damage, reduction of ATP, oxidative stress, and apoptosis of the cardiomyocytes. Cardiomyocytes, as cells with high energy demand, rely greatly on mitochondrial homeostasis and ATP production. Thus, therapeutic intervention to specifically target the mitochondria and ATP production can potentially alleviate ACM. Mitochonic acid 5 (MA-5) has been recently identified as a potential therapeutic compound that increases cellular ATP and improves mitochondrial function in several cardiac disorders. Given the potential role of MA-5 in improving mitochondrial function, I speculate that MA-5 could be an effective treatment for alcohol-induced cardiotoxicity. In the present study, I test the hypothesis that MA-5 can mitigate mitochondrial energetics in cultured cardiomyocytes exposed to alcohol. To investigate this, neonatal mouse cardiomyocytes (NMCMs) were isolated from mice at day 1-2 of age and cultured for 6 days with alcohol (50mM). The cells were treated with MA-5 (1μM, 5μM, or 10μM) for 4 hours with serum starvation and then cellular energetic changes were measured using the Mito Stress assay with the Seahorse Bioanalyzer (XF96pro, Agilent). To investigate the impacts of chronic alcohol exposure, rat embryonic myoblasts, H9C2 cells, were treated with 50mM alcohol for 3 weeks. Subsequently, cells were treated with MA-5 (1μM, 5μM, or 10μM) for 24 hours and then attached to the Resipher system (Lucid Lab) for continuous oxygen consumption monitoring and recording. NMCMs treated with 50mM alcohol showed a substantial reduction in basal respiration, maximal respiration, and spare respiratory capacity compared to controls. NMCMs treated with 10μM MA-5 showed a significant improvement in these parameters. Chronically exposed H9C2 cells showed a prolonged decline in OCR. MA-5 treatment improved and maintained oxygen consumption in these cells. In summary, these results demonstrated that alcohol exposed cardiomyocytes experience a decline in cellular energetics that could be corrected by MA-5 treatment. Future in vivo studies on preclinical ACM animal models are warranted to yield further insights into a potential novel therapy for ACM in patients. This research was supported by grant #T32AA007577 from the NIAAA at the National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.