Mitolnc controls cardiac BCAA metabolism and heart hypertrophy by allosteric activation of BCKDH.
Nucleic Acids Res
; 52(11): 6629-6646, 2024 Jun 24.
Article
de En
| MEDLINE
| ID: mdl-38567728
ABSTRACT
Enzyme activity is determined by various different mechanisms, including posttranslational modifications and allosteric regulation. Allosteric activators are often metabolites but other molecules serve similar functions. So far, examples of long non-coding RNAs (lncRNAs) acting as allosteric activators of enzyme activity are missing. Here, we describe the function of mitolnc in cardiomyocytes, a nuclear encoded long non-coding RNA, located in mitochondria and directly interacting with the branched-chain ketoacid dehydrogenase (BCKDH) complex to increase its activity. The BCKDH complex is critical for branched-chain amino acid catabolism (BCAAs). Inactivation of mitolnc in mice reduces BCKDH complex activity, resulting in accumulation of BCAAs in the heart and cardiac hypertrophy via enhanced mTOR signaling. We found that mitolnc allosterically activates the BCKDH complex, independent of phosphorylation. Mitolnc-mediated regulation of the BCKDH complex constitutes an important additional layer to regulate the BCKDH complex in a tissue-specific manner, evading direct coupling of BCAA metabolism to ACLY-dependent lipogenesis.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Cardiomégalie
/
ARN long non codant
/
Acides aminés à chaine ramifiée
Limites:
Animals
/
Humans
/
Male
Langue:
En
Journal:
Nucleic Acids Res
Année:
2024
Type de document:
Article
Pays d'affiliation:
Allemagne
Pays de publication:
Royaume-Uni