Xu Xihui, Penjweini Rozhin, Székvölgyi Lóránt, Karányi Zsolt, Heckel Anne-Marie, Gurusamy Devikala, Varga Dóra, Yang Shutong, Brown Alexandra L, Cui Wenqi, Park Jinsung, Nagy Dénes, Podszun Maren C, Yang Sarah, Singh Komudi, Ashcroft Stephen P, Kim Jeonghan, Kim Myung K, Tarassov Ivan, Zhu Jun, Philp Andrew, Rotman Yaron, Knutson Jay R, Entelis Nina, Chung Jay H
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892.
Laboratory of Advanced Microscopy and Biophotonics, Biochemistry and Biophysics Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2411298122. doi: 10.1073/pnas.2411298122. Epub 2025 Jan 3.
Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known. Fat accumulation in metabolic dysfunction-associated steatotic liver disease (MASLD), which is more common in men, is caused in part by mitochondrial dysfunction. EndoG expression is reduced in MASLD liver, and EndoG deficiency causes MASLD in an obesity-independent manner but only in males. EndoG promotes mitochondrial respiration by resolving mitochondrial tRNA/DNA hybrids formed during mtDNA transcription by recruiting RNA helicase DHX30 to unwind them. EndoG also cleaves off the 3'-end of the H-strand transcript that can prevent mt-tRNA precursor cloverleaf-folding, and processing, which increases mt-tRNA production and mitochondrial translation. Using fluorescent lifetime imaging microscopy technology to visualize oxygen consumption at the individual mitochondrion level, we found that EndoG deficiency leads to the selective loss of a mitochondrial subpopulation with high-oxygen consumption. This defect was reversed with mt-tRNA supplementation. Thus, EndoG promotes mitochondrial respiration by selectively regulating the production of mt-tRNA in male mice.
线粒体核酸内切酶G（EndoG）在细胞凋亡过程中从线粒体释放时会导致染色体降解。由于EndoG缺乏会导致线粒体功能障碍，因此推测它也具有线粒体功能。然而，EndoG调节线粒体功能的机制尚不清楚。代谢功能障碍相关脂肪性肝病（MASLD）中的脂肪堆积在男性中更为常见，部分原因是线粒体功能障碍。MASLD肝脏中EndoG表达降低，EndoG缺乏以不依赖肥胖的方式导致MASLD，但仅在雄性中出现。EndoG通过招募RNA解旋酶DHX30解开线粒体DNA转录过程中形成的线粒体tRNA/DNA杂交体，从而促进线粒体呼吸。EndoG还切割H链转录本的3'末端，该末端可阻止线粒体tRNA前体的三叶草折叠和加工，从而增加线粒体tRNA的产生和线粒体翻译。使用荧光寿命成像显微镜技术在单个线粒体水平上可视化氧气消耗，我们发现EndoG缺乏导致具有高耗氧量的线粒体亚群选择性丧失。补充线粒体tRNA可逆转这一缺陷。因此，EndoG通过选择性调节雄性小鼠线粒体tRNA的产生来促进线粒体呼吸。
