Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression

Alisson C. Cardoso, Nicholas T. Lam, Jainy J. Savla, Yuji Nakada, Ana Helena M. Pereira, Abdallah Elnwasany, Ivan Menendez-Montes, Emily L. Ensley, Ursa Bezan Petric, Gaurav Sharma, A. Dean Sherry, Craig R. Malloy, Chalermchai Khemtong, Michael T. Kinter, Wilson Lek Wen Tan, Chukwuemeka G. Anene-Nzelu, Roger Sik Yin Foo, Ngoc Uyen Nhi Nguyen, Shujuan Li, Mahmoud Salama AhmedWaleed M. Elhelaly, Salim Abdisalaam, Aroumougame Asaithamby, Chao Xing, Mohammed Kanchwala, Gonçalo Vale, Kaitlyn M. Eckert, Matthew A. Mitsche, Jeffrey G. McDonald, Joseph A. Hill, Linzhang Huang, Philip W. Shaul, Luke I. Szweda, Hesham A. Sadek

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.

Original languageEnglish (US)
Pages (from-to)167-178
Number of pages12
JournalNature Metabolism
Volume2
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

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  • Cite this

    Cardoso, A. C., Lam, N. T., Savla, J. J., Nakada, Y., Pereira, A. H. M., Elnwasany, A., Menendez-Montes, I., Ensley, E. L., Bezan Petric, U., Sharma, G., Sherry, A. D., Malloy, C. R., Khemtong, C., Kinter, M. T., Tan, W. L. W., Anene-Nzelu, C. G., Foo, R. S. Y., Nguyen, N. U. N., Li, S., ... Sadek, H. A. (2020). Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression. Nature Metabolism, 2(2), 167-178. https://doi.org/10.1038/s42255-020-0169-x