Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling
Jessica Gambardella1,2,3, Stanislovas S Jankauskas1, Urna Kansakar1
1Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, New York, New York, USA.
Insights
Researchers discovered a specific histone modification (H3_K27me2K36me1) that worsens heart injury after ischemia. Ketone bodies, like beta-hydroxybutyrate, show potential in reversing this damage and improving mitochondrial function.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Ischemic cardiac disease remains a leading global cause of mortality.
- The precise molecular mechanisms driving post-ischemic heart failure (HF) are not fully elucidated.
- Understanding these mechanisms is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify molecular alterations in the heart following ischemic injury.
- To investigate the role of chromatin remodeling in the pathogenesis of post-ischemic HF.
- To explore potential therapeutic interventions targeting identified molecular pathways.
Main Methods:
- Utilized in vivo and in vitro experimental models, including human cardiac specimens, a murine HF model, and cellular systems.
- Employed molecular biology techniques to analyze histone modifications and gene expression.
- Assessed the impact of beta-hydroxybutyrate treatment on cellular and molecular parameters.
Main Results:
- Identified a novel epigenetic signature, H3_K27me2K36me1, consistently induced by ischemic injury in all models studied.
- Demonstrated that this histone modification epigenetically represses the master mitochondrial regulator PGC1α.
- Showed that beta-hydroxybutyrate treatment attenuates H3_K27me2K36me1 and improves mitochondrial dysfunction.
Conclusions:
- Maladaptive chromatin remodeling, specifically H3_K27me2K36me1, is a key mechanism in post-ischemic heart injury.
- The repression of PGC1α by this epigenetic modification contributes to mitochondrial dysfunction.
- Ketone bodies represent a promising therapeutic avenue for mitigating ischemic heart injury by modulating metabolism-gene expression pathways.
Abstract:
Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.
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