Max Planck Institute for Heart- and Lung Research, Department of Cardiac Development and Remodelling, Ludwigstr. 43, D-61231 Bad Nauheim, Germany.
Nucleic Acids Res. 2024 Jun 24;52(11):6629-6646. doi: 10.1093/nar/gkae226.
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.
酶活性受多种不同机制的影响，包括翻译后修饰和变构调节。变构激活剂通常是代谢物，但其他分子也具有类似的功能。到目前为止，还没有长链非编码 RNA（lncRNA）作为酶活性变构激活剂的例子。在这里，我们描述了位于线粒体中的核编码长链非编码 RNA mitolnc 在心肌细胞中的功能，它直接与支链酮酸脱氢酶（BCKDH）复合物相互作用，增加其活性。BCKDH 复合物对支链氨基酸（BCAAs）的分解代谢至关重要。在小鼠中敲除 mitolnc 会降低 BCKDH 复合物的活性，导致心脏中 BCAAs 的积累，并通过增强 mTOR 信号导致心脏肥大。我们发现 mitolnc 变构激活 BCKDH 复合物，不依赖于磷酸化。mitolnc 对 BCKDH 复合物的调节构成了一个重要的附加层，以组织特异性的方式调节 BCKDH 复合物，避免了 BCAA 代谢与 ACLY 依赖性脂肪生成的直接偶联。
