The Role of Cardiomyocyte Mitochondrial AMPK and ATP Synthase in Hypertrophic Cardiomyopathy (HCM)
Introduction. Hypertrophic Cardiomyopathy (HCM) is a cardiovascular disease affecting 1 in 500 people where heart muscle becomes abnormally thick.1 HCM can manifest as a left ventricular outflow tract obstruction, left ventricular hypertrophy, or a non-obstructive form with wall thinning and dilation of the cavity.1 HCM is characterized by (1) endomitosis, pathologic growth of multinucleated cardiomyocytes,4 (2) endoreplication, duplication of nuclear DNA without mitosis,4 and (3) deregulation of ADP:ATP levels.2,4 HCM is diagnosed out of exclusion, and treatments include lifestyle adjustments, symptomatic medicines, pacemakers, and a septal myectomy. Previous studies have shown that ATP synthase is a central node in the control of cardiac endoreplication.2 Methods. Studies analyzed included varied methods. Several studies induced HCM in mice models using trans-aortic constructions or aortic banding. 2,4-6 Some used sh-RNAs with Mlc2v-Cre transgenic mice to selectively knock-out proteins of interest.2 Others used cultured rat myoblast H9C2 cells and C57BL/6J mice.5,6 Left ventricular sections were taken by biopsy from human subjects as well. Studies that analyzed the effect of Aconitine and Hispidulin on cardiomyocytes used serial dilutions.4,6 Results. Expression of ATP synthase subunits were correlated with markers of cardiac hypertrophy and dysfunction in humans and mice. ATP5a1 was found to have the strongest correlation in both settings.2 ATP5a1 KO mice had reduced cardiac hypertrophy, fibrosis, and contractile dysfunction, reduced ATP and increased ADP:ATP ratio.2 MTHFD1L was found to be a key rate-limiting enzyme and intermediate in the AMPK-ATP5a1 pathway as well as the pathway for de-novo nucleotide synthesis. Mice with knockouts of MTHFD1L/ATP5a1 were protected from pressure overload-induced HCM, proving that MTHFD1L is necessary for pathologic HCM.2 In another study, less than 5 µmol of Aconitine was found to disturb mitochondrial homeostasis and upregulate ATP5a1 in vitro.4 Calpain was also found to modulate myocardial injury, and in H9C2 rats, overexpression of Calpastatin led to cardiomyopathy.5 Hispidulin was tested on C57BL/6J mice and was found to prevent pathologic cardiac hypertrophy and improve cardiac function in vivo. Conclusions. A causative link had not been previously established between mitochondria and HCM. Recent studies identified the ATP5a1-AMPk pathway as a key intermediate in the development of HCM in mitochondria of cardiomyocytes through key intermediates such as MTHFD1, OPA1, Sirt1, and Calpain. Several modulators of the pathway and potential therapeutics have been identified, including Aconitine, Calpastatin, and Hispidulin.
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- Bischof C, Mirtschink P, Yuan T, et al. Mitochondrial–cell cycle cross-talk drives endoreplication in heart disease. Science Translational Medicine. 2021;13(623). doi:10.1126/scitranslmed.abi7962
- Nomura, S., Satoh, M., Fujita, T. et al. Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. Nat Commun 9, 4435 (2018). https://doi.org/10.1038/s41467-018-06639-7
- Qiu LZ, Zhou W, Yue LX, et al. Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK-OPA1-ATP5A1 Pathway. Front Pharmacol. 2021;12:646121. Published 2021 Jun 10. doi:10.3389/fphar.2021.646121
- Zheng D, Cao T, Zhang LL, Fan GC, Qiu J, Peng TQ. Targeted inhibition of calpain in mitochondria alleviates oxidative stress-induced myocardial injury. Acta Pharmacol Sin. 2021;42(6):909-920. doi:10.1038/s41401-020-00526-y
- Wang Y, Xie Z, Jiang N, et al. Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction. Front Cardiovasc Med. 2020;7:582890. Published 2020 Nov 26. doi:10.3389/fcvm.2020.582890