Mitochondria regulate proliferation in adult cardiac myocytes
Gregory B. Waypa, … , Edward B. Thorp, Paul T. Schumacker
Gregory B. Waypa, … , Edward B. Thorp, Paul T. Schumacker
Published May 9, 2024
Citation Information: J Clin Invest. 2024;134(13):e165482. https://doi.org/10.1172/JCI165482.
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Research Article Cardiology Metabolism

Mitochondria regulate proliferation in adult cardiac myocytes

Abstract

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Authors

Gregory B. Waypa, Kimberly A. Smith, Paul T. Mungai, Vincent J. Dudley, Kathryn A. Helmin, Benjamin D. Singer, Clara Bien Peek, Joseph Bass, Lauren Nelson, Sanjiv J. Shah, Gaston Ofman, J. Andrew Wasserstrom, William A. Muller, Alexander V. Misharin, G.R. Scott Budinger, Hiam Abdala-Valencia, Navdeep S. Chandel, Danijela Dokic, Elizabeth Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B. Thorp, Paul T. Schumacker

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Figure 10

Epigenetic analysis of RISP-WT and -KO hearts.

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Epigenetic analysis of RISP-WT and -KO hearts. (A) Left: Cumulative dist...
(A) Left: Cumulative distribution of DNA CpG methylation in RISP-WT (blue) and -KO (red) hearts. Right: Box-and-whisker plot showing significant increase in DNA CpG methylation (DMC) in RISP-KO compared with WT hearts (P < 0.0001, Kolmogorov-Smirnov test). Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). (B) Venn diagram comparing differentially expressed genes (DEGs) and differentially methylated DNA CpG sites located in regulatory regions of genes reveals an overlap of 115 genes. (C) K-means clustering of RNA-Seq identification of 115 DEG and DMC genes showing directional change (upregulated, red, versus downregulated, blue) in RISP-KO (n = 4) versus WT hearts (n = 4). (D) K-means clustering after filtering was applied to restrict the data set to CpGs with 25% higher methylation in lower expression groups compared with higher expression groups. This identified 93 DEG and DMC genes in RISP-KO (n = 4) versus WT hearts. (E) DNA CpG methylation status of 93 DEGs and DMCs showing that downregulated genes are more highly methylated (green) in regulatory regions, while upregulated genes are less highly methylated (violet), in RISP KO compared with WT. For C–E, DEGs were determined by a generalized linear model and ANOVA-like testing with FDR q value less than 0.05, and DMCs were determined by a β-binomial regression model with an arcsine link function fitted using the generalized least-squares method and Wald test FDR q value less than 0.05.