TY - JOUR
T1 - Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling
AU - Gambardella, Jessica
AU - Jankauskas, Stanislovas S.
AU - Kansakar, Urna
AU - Varzideh, Fahimeh
AU - Avvisato, Roberta
AU - Prevete, Nella
AU - Sidoli, Simone
AU - Mone, Pasquale
AU - Wang, Xujun
AU - Lombardi, Angela
AU - Santulli, Gaetano
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - BHB
KW - heart failure
KW - histone methylation
KW - ischemia
KW - mitochondria
KW - myocardial infarction
KW - β-hydroxybutyrate
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UR - http://www.scopus.com/inward/citedby.url?scp=85152696723&partnerID=8YFLogxK
U2 - 10.1016/j.jacbts.2023.03.014
DO - 10.1016/j.jacbts.2023.03.014
M3 - Article
AN - SCOPUS:85152696723
SN - 2452-302X
VL - 8
SP - 1123
EP - 1137
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 9
ER -