Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNA <sup>Thr</sup> production
Abstract
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 Thr precursor cloverleaf-folding, and processing, which increases mt-tRNA Thr 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 Thr supplementation. Thus, EndoG promotes mitochondrial respiration by selectively regulating the production of mt-tRNA Thr in male mice.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Xihui Xu
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Rozhin Penjweini
Lóránt Székvölgyi
Momentum Genome Architecture and Recombination Research Group, Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen
Zsolt Karányi
Momentum Genome Architecture and Recombination Research Group, Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen
Anne-Marie Heckel
UMR 7156 Génétique Moléculaire, Génomique, Microbiologie, Strasbourg University-CNRS
Devikala Gurusamy
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Dóra Varga
Momentum Genome Architecture and Recombination Research Group, Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen
Shutong Yang
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Alexandra L. Brown
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Wenqi Cui
Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases
Jinsung Park
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Dénes Nagy
Momentum Genome Architecture and Recombination Research Group, Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen
Maren C. Podszun
Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases
Sarah Yang
DNA Sequencing and Genomics Core Facility, National Heart Lung and Blood Institute, NIH
Komudi Singh
Bioinformatics Core Facility, National Heart Lung and Blood Institute, NIH
Stephen P. Ashcroft
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Jeonghan Kim
Department of Biochemistry, College of Medicine, The Catholic University of Korea
Myung K. Kim
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH
Ivan Tarassov
UMR 7156 Génétique Moléculaire, Génomique, Microbiologie, Strasbourg University-CNRS
Jun Zhu
Wuxi EliTe Solar Co., Wuxi, China.
Andrew Philp
Centre for Healthy Ageing, Centenary Institute, Royal Prince Alfred Hospital
Yaron Rotman
Jay R. Knutson
Nina Entelis
UMR 7156 Génétique Moléculaire, Génomique, Microbiologie, Strasbourg University-CNRS
Jay H. Chung
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH