| First Author | Jin Z | Year | 2014 |
| Journal | Cell Metab | Volume | 20 |
| Issue | 3 | Pages | 483-98 |
| PubMed ID | 25130399 | Mgi Jnum | J:215568 |
| Mgi Id | MGI:5605632 | Doi | 10.1016/j.cmet.2014.07.011 |
| Citation | Jin Z, et al. (2014) Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab 20(3):483-98 |
| abstractText | 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. |
