Mitochondria Regulate Proliferation in Adult Cardiac Myocytes

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

Publication Date

5-9-2024

Journal

The Journal of Clinical Investigation

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.

Keywords

Animals, Myocytes, Cardiac, Mice, Cell Proliferation, Mitochondria, Heart, Mice, Knockout, Electron Transport Complex III, Glucose, Cardiology, Metabolism, Bioenergetics, Cardiovascular disease, Mitochondria

Comments

Supplementary Materials

PMID: 38722697