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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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 3

Cardiac RISP deletion causes cardiac hyperplasia.

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Cardiac RISP deletion causes cardiac hyperplasia. (A) Isolated, individu...
(A) Isolated, individual cardiomyocytes from mT/mG-RISP-WT or -KO mice 60 days after tamoxifen were stained with DAPI. Cardiomyocytes from mT/mG-RISP-WT mice maintained red fluorescence (mT), while cardiomyocytes from mT/mG-RISP-KO mice expressed green fluorescence (mG). The length and width of Cre-activated cardiomyocytes expressing mG were measured (ImageJ). Scale bars: 25 μm. (B and C) Cardiomyocyte length (B) and width (C). RISP KO had no effect on the size of cardiomyocytes compared with WT. (D) RISP KO caused cardiac hyperplasia compared with WT, as assessed by number of cardiomyocytes in hearts. Cardiomyocytes were counted and extrapolated to determine the number in the whole heart; n = 6–10 mice per condition, mean ± SEM, unpaired 2-tailed t test. (E) RISP KO increased the percentage of mononucleated and decreased the percentage of binucleated cardiomyocytes compared with WT. DAPI-stained cardiomyocytes were imaged and designated as mononucleated, binucleated, or polynucleated. Nuclei count is reported as percentage of assessed cardiomyocytes. (F) RISP KO increased the total number of nuclei compared with WT. Graph represents total number of nuclei per mouse heart and distribution of those nuclei across mono-, bi-, and polynucleated cardiomyocytes. For B, C, E, and F, approximately 40–45 cardiomyocytes per mouse were measured and averaged; n = 6–10 mice per condition, mean ± SEM, unpaired 2-tailed t test. ****P < 0.0001. (G) Diagram illustrating why cardiac wall thickness did not increase markedly in RISP-KO hearts undergoing hyperplastic remodeling. Cardiomyocytes appear to divide and grow in an end-to-end direction rather than side to side (with no difference in cell lengths), resulting in greater circumference of the heart wall without a large increase in LV wall thickness, a significant increase in the widths of cells, or an increase in number of cells across the LV free wall.