Sudha B. SinghWojciech OrnatowskiIsabelle VergneJohn NaylorMonica DelgadoEsteban RobertsMarisa PonpuakSharon MasterManohar PilliEileen WhiteMasaaki KomatsuVojo DereticUniversity of New Mexico Health Sciences CenterMahidol UniversityThe Cancer Institute of New JerseyTokyo Metropolitan Institute of Medical ScienceJuntendo University School of Medicine2018-09-242018-09-242010-12-01Nature Cell Biology. Vol.12, No.12 (2010), 1154-1165146573922-s2.0-78649833818https://repository.li.mahidol.ac.th/handle/20.500.14594/28590IRGM, a human immunity-related GTPase, confers autophagic defence against intracellular pathogens by an unknown mechanism. Here, we report an unexpected mode of IRGM action. IRGM demonstrated differential affinity for the mitochondrial lipid cardiolipin, translocated to mitochondria, affected mitochondrial fission and induced autophagy. Mitochondrial fission was necessary for autophagic control of intracellular mycobacteria by IRGM. IRGM influenced mitochondrial membrane polarization and cell death. Overexpression of IRGMd, but not IRGMb splice isoforms, caused mitochondrial depolarization and autophagy-independent, but Bax/Bak-dependent, cell death. By acting on mitochondria, IRGM confers autophagic protection or cell death, explaining IRGM action both in defence against tuberculosis and in the damaging inflammation caused by Crohn's disease. © 2010 Macmillan Publishers Limited. All rights reserved.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/ncb2119