title: Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization.
abstract: Mitochondrial complex I (CI) deficiency is associated with multiple neurological and metabolic disorders. However, its effect on innate immunity and bone remodeling is unclear. Using deletion of the essential CI subunit Ndufs4 as a model for mitochondrial dysfunction, we report that mitochondria suppress macrophage activation and inflammation while promoting osteoclast differentiation and bone resorption via both cell-autonomous and systemic regulation. Global Ndufs4 deletion causes systemic inflammation and osteopetrosis. Hematopoietic Ndufs4 deletion causes an intrinsic lineage shift from osteoclast to macrophage. Liver Ndufs4 deletion causes a metabolic shift from fatty acid oxidation to glycolysis, accumulating fatty acids and lactate (FA/LAC) in the circulation. FA/LAC further activates Ndufs4(-/-) macrophages via reactive oxygen species induction and diminishes osteoclast lineage commitment in Ndufs4(-/-) progenitors; both inflammation and osteopetrosis in Ndufs4(-/-) mice are attenuated by TLR4/2 deletion. Together, these findings reveal mitochondrial CI as a critical rheostat of innate immunity and skeletal homeostasis.
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yihong.wan@utsouthwestern.edu.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000505:Alopecia / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D001862:Bone Resorption / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006019:Glycolysis; D007113:Immunity, Innate; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I