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Citations to this article

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 Article has an altmetric score of 114

Mitochondria regulate proliferation in adult cardiac myocytes

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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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Total citations by year

Year: 2025 2024 Total
Citations: 4 3 7
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article (7)

Title and authors Publication Year
Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation.
Koopmans T, van Rooij E
Nature reviews. Cardiology 2025
Mercury-Mediated Cardiovascular Toxicity: Mechanisms and Remedies.
Amin A, Saadatakhtar M, Mohajerian A, Marashi SM, Zamanifard S, Keshavarzian A, Molaee P, Keshmiri MS, Nikdoust F
Cardiovascular toxicology 2025
The flux of energy in critical illness and the obesity paradox
Jaitovich A, Hall JB
Physiological reviews 2025
Sulfide regulation and catabolism in health and disease
Hou Y, Lv B, Du J, Ye M, Jin H, Yi Y, Huang Y
Signal Transduction and Targeted Therapy 2025
Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
Balnis J, Tufts A, Jackson EL, Drake LA, Singer DV, Lacomis D, Lee CG, Elias JA, Doles JD, Maher LJ 3rd, Jen A, Coon JJ, Jourd'heuil D, Singer HA, Vincent CE, Jaitovich A
Science advances 2024
The impact of aging on cardiac repair and regeneration
Anwar I, Wang X, Pratt RE, Dzau VJ, Hodgkinson CP
The Journal of Biological Chemistry 2024
Functional transformation of macrophage mitochondria in cardiovascular diseases.
Wei J, Peng MY, Lu HX
Molecular and cellular biochemistry 2024

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