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ResearchIn-Press PreviewCardiologyMetabolism Open Access | 10.1172/JCI165482
1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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1Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America
3Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States of America
4Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
5Department of Biochemistry and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America
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Published May 9, 2024 - More info
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, they 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-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-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.