Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation (OXPHOS) but loses mitotic capacity. The exploration of forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype as a method to restore proliferative capacity is a promising area of research. In a significant study, Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) was deleted in the hearts of adult mice. This genetic alteration led to a decline in mitochondrial function and an increase in glucose utilization. Remarkably, these hearts underwent hyperplastic remodeling, resulting in a doubling of cardiomyocyte numbers without cellular hypertrophy. This article delves into the intricate processes and findings of this study, elucidating the potential for therapeutic cardiac regeneration.
The Role of Mitochondria in Cardiomyocytes
Mitochondria are pivotal in ATP generation through OXPHOS, a function critical in metabolically active tissues like the heart. However, mitochondria also engage in redox signaling, metabolite signaling, calcium signaling, and generating stress signals that affect distant tissues. They synthesize biomolecules involved in the epigenetic modification of histones and DNA, and produce substrates needed for lipid, protein, and nucleotide biosynthesis necessary for biomass generation in proliferating cells.
In fetal hearts, where oxygen tension is low, mitochondrial OXPHOS is underdeveloped, and cardiomyocytes rely primarily on glycolysis for energy production. Post-birth, heart cells transition from glycolysis to mitochondrial respiration, enhancing ATP production to meet increased metabolic demands. This transition coincides with a loss of mitotic capacity in cardiomyocytes, a characteristic of the adult heart.
Hypothesis and Experimental Design
The hypothesis posited that reverting adult cardiomyocytes to a glycolytic state could restore their proliferative capacity. To test this, researchers genetically disrupted mitochondrial function by deleting the Uqcrfs1 gene in adult mouse hearts. This gene encodes RISP, a component of complex III essential for electron transfer and proton translocation. Previous studies have shown that this gene is dispensable for cell survival in other tissues, suggesting mitochondria’s roles beyond ATP production.
The deletion of Uqcrfs1 was anticipated to cause a gradual shift towards glycolysis as mitochondrial turnover led to the disappearance of existing RISP protein, providing a window for cells to adjust to this metabolic transition.
Key Findings
Mitochondrial Function and Glucose Utilization
Genetic deletion of Uqcrfs1 resulted in a progressive loss of RISP protein, leading to diminished mitochondrial function. This was accompanied by an upregulation of glycolysis, evidenced by increased glucose uptake and tissue lactate and pyruvate levels. Despite the decline in OXPHOS, energy stores were maintained, bioenergetic stress was absent, and AMPK activation did not occur. Notably, mTOR activation was evident, indicating cellular energy supply was preserved.
Hyperplastic Remodeling and Cardiomyocyte Proliferation
The study observed hyperplastic remodeling in the hearts of RISP-deleted mice, characterized by a doubling of cardiomyocyte numbers without cellular hypertrophy. This proliferation was evidenced by increased nuclear staining for Ki-67 and phospho-histone H3, higher EdU staining in vivo, and a significant rise in cardiomyocyte nuclei. These changes indicate that RISP deletion induced a developmental regression to a perinatal state, marked by increased glycolysis and restored mitotic capacity but decreased contractile function.
Gene Expression and Epigenetic Modifications
RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation, alongside downregulation of genes linked to contractile function. Metabolomic analysis showed a decrease in alpha-ketoglutarate (necessary for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). This led to increased methylated CpGs near gene transcriptional start sites. Genes that were differentially expressed and methylated were linked to upregulated cardiac developmental pathways, suggesting that metabolic shifts influenced epigenetic modifications, promoting cardiomyocyte proliferation.
Implications for Cardiac Regeneration
In ischemic hearts with RISP deletion, new cardiomyocytes migrated into infarcted regions, indicating potential for therapeutic cardiac regeneration. Despite the progressive decline in cardiac function leading to eventual heart failure, these findings highlight a crucial step towards understanding how metabolic and epigenetic modulation can restore cardiomyocyte proliferation.
Comparison with Previous Studies
Previous studies have linked complex III dysfunction in mitochondrial cardiomyopathies to hypertrophic remodeling. However, the gene expression profiles of RISP KO hearts did not resemble those of hypertrophic or dilated cardiomyopathy. Furthermore, the cellular morphology and cardiac structure in RISP KO hearts did not align with classical hypertrophic or dilated cardiomyopathy. Instead, these hearts exhibited characteristics of a novel hyperplastic remodeling process.
Discussion
The research presented here provides compelling evidence that forced metabolic reversion to a glycolytic phenotype can restore the proliferative capacity of adult cardiomyocytes. This process involves a complex interplay between mitochondrial function, cellular metabolism, and epigenetic regulation. By decreasing mitochondrial function and increasing glucose utilization, adult cardiomyocytes can re-enter the cell cycle and proliferate, potentially leading to new therapeutic strategies for cardiac regeneration.
Metabolic and Epigenetic Interactions
The increase in glycolysis and the resultant metabolic changes promoted DNA methylation, influencing gene expression patterns essential for cardiomyocyte proliferation. This indicates that metabolic modulation can have profound effects on cellular epigenetics, driving changes in cell fate and function.
Metabolic and Epigenetic Interactions Explained Simply
Imagine your heart cells have two different ways to get energy: a quick and easy way (like eating sugar) called glycolysis, and a slow but powerful way (like eating a big meal) called mitochondrial function. When heart cells switch from the quick way to the powerful way, they stop multiplying.
In the study, scientists found that if they make heart cells switch back to using the quick way, the cells can start multiplying again. This switch changes not just how the cells get energy but also affects little tags on the cell’s DNA called methylation. These tags can turn genes on or off, much like how light switches control lights in a house.
When the heart cells start using the quick energy way again, it changes these tags, which turns on genes that tell the cells to multiply. This means that by changing how cells get energy, scientists can also change which genes are active, helping the cells to grow and repair the heart. So, the way cells process energy can actually change their behavior and function.
Therapeutic Potential and Future Directions
The ability of new cardiomyocytes to migrate into infarcted regions presents a significant opportunity for developing therapies aimed at repairing damaged hearts. Future studies should explore whether restoring Uqcrfs1 expression in injured hearts can reverse the contractile deficits and leverage the newly formed cardiomyocytes for functional recovery.
Conclusion
This study illuminates the intricate relationship between mitochondrial function, cellular metabolism, and epigenetic regulation in cardiomyocytes. By manipulating these pathways, it is possible to restore the proliferative capacity of adult heart cells, opening new avenues for therapeutic cardiac regeneration. The findings underscore the potential of metabolic and epigenetic modulation in developing innovative treatments for heart disease, offering hope for patients with ischemic heart injuries and other cardiac conditions. Further research is needed to fully harness this potential and translate these findings into clinical applications.
reference link: https://www.jci.org/articles/view/165482
