Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production

• 成果类型: Article
• 署名作者: Xu, Xihui; Penjweini, Rozhin; Szekvolgyi, Lorant; Karanyi, Zsolt; Heckel, Anne- Marie; Gurusamy, Devikala; Varga, Dora; Yang, Shutong; Brown, Alexandra L.; Cui, Wenqi; Park, Jinsung; Nagy, Denes; 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.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); University of Debrecen; University of Debrecen; Centre National de la Recherche Scientifique (CNRS); Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); University of Birmingham; Catholic University of Korea; Catholic University of Korea; University of Sydney; NSW Health; Royal Prince Alfred Hospital; University of Technology Sydney
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15085
• DOI: 10.1073/pnas.2411298122
• 发表日期: 2025-01-07
• 关键词: fatty liver-disease; r-loops; Mutation; tissues; melas

摘要

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- tRNAThr precursor cloverleaf- folding, and processing, which increases mt- tRNAThr 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- tRNAThr supplementation. Thus, EndoG promotes mitochondrial respiration by selectively regulating the production of mt- tRNAThr in male mice.