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.
| Original language | English (US) |
|---|---|
| Article number | e165482 |
| Journal | Journal of Clinical Investigation |
| Volume | 134 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jul 1 2024 |
Funding
This work was supported by NIH grants HL35440, HL122062, HL118491, and HL109478 (to PTS). The authors thank Joann Taylor for technical assistance, and Meryl R. Schumacker for editorial assistance with the manuscript. RNA-Seq analysis was performed in the High-Throughput RNA-Seq Lab, Division of Pulmonary and Critical Care Medicine, Northwestern University. The Genomics Computing Cluster is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, Feinberg\u2019s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology and maintained and developed by Feinberg IT and Research Computing Group. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by National Cancer Institute (NCI) grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Electron microscopy was performed in the Northwestern University Center for Advanced Microscopy and Nikon Imaging Center, funded by a Cancer Center Support Grant (CCSG) P30 grant (CA060553). Flow cytometry was supported by the Northwestern University Flow Cytometry Core Facility supported by a CCSG (NCI-CA060553). FDG-PET imaging work was performed at the Northwestern University Center for Advanced Molecular Imaging supported by NCI CCSG P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The myocardial infarction surgeries were performed by the Microsurgery and Preclinical Research Core at the Comprehensive Transplant Center of Northwestern University Feinberg School of Medicine. Metabolomic analyses were performed by Metabolon Inc. Mouse genotyping was performed by Transnetyx Inc. This work was supported by NIH grants HL35440, HL122062, HL118491, and HL109478 (to PTS). The authors thank Joann Taylor for technical assistance, and Meryl R. Schumacker for editorial assistance with the manuscript. RNA-Seq analysis was performed in the High-Throughput RNA-Seq Lab, Division of Pulmonary and Critical Care Medicine, Northwestern University. The Genomics Computing Cluster is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, Feinberg\u2019s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology and maintained and developed by Feinberg IT and Research Computing Group. Histology services were provided by the North-western University Mouse Histology and Phenotyping Laboratory, which is supported by National Cancer Institute (NCI) grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Electron microscopy was performed in the Northwestern University Center for Advanced Microscopy and Nikon Imaging Center, funded by a Cancer Center Support Grant (CCSG) P30 grant (CA060553). Flow cytometry was supported by the North-western University Flow Cytometry Core Facility supported by a CCSG (NCI-CA060553). FDG-PET imaging work was performed at the Northwestern University Center for Advanced Molecular Imaging supported by NCI CCSG P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The myocardial infarction surgeries were performed by the Microsurgery and Preclinical Research Core at the Comprehensive Transplant Center of Northwestern University Feinberg School of Medicine. Metabolom-ic analyses were performed by Metabolon Inc. Mouse genotyping was performed by Transnetyx Inc.
ASJC Scopus subject areas
- General Medicine