RESUMO
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.
Assuntos
Aminoácidos de Cadeia Ramificada , Cardiomegalia , RNA Longo não Codificante , Animais , Regulação Alostérica , Camundongos , Cardiomegalia/metabolismo , Cardiomegalia/genética , Aminoácidos de Cadeia Ramificada/metabolismo , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Miócitos Cardíacos/metabolismo , Humanos , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Transdução de Sinais , Camundongos Endogâmicos C57BL , Serina-Treonina Quinases TOR/metabolismo , Masculino , Camundongos KnockoutRESUMO
Chromatin remodeling complexes have functions in transcriptional regulation and chromosome maintenance, but it is mostly unknown how the function of these normally ubiquitous complexes is specified in the cellular context. Here, we describe that the evolutionary conserved long non-coding RNA linc-MYH regulates the composition of the INO80 chromatin remodeler complex in muscle stem cells and prevents interaction with WDR5 and the transcription factor YY1. Linc-MYH acts as a selective molecular switch in trans that governs the pro-proliferative function of the ubiquitous INO80 complex but does not affect its role in maintaining genomic stability. The molecular switch is essential for restricting generation of quiescent MuSCs and proliferation of myoblasts in homeostasis and regeneration. Since linc-MYH is expressed in proliferating myoblasts but not in quiescent MuSCs, we reason that the extent of myoblast proliferation has decisive effects on the size of the quiescent MuSC pool.
