Mitochondrial complex i activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization

Zixue Jin, Wei Wei, Marie Yang, Yang Du, Yihong Wan

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)483-498
Number of pages16
JournalCell Metabolism
Volume20
Issue number3
DOIs
StatePublished - Sep 2 2014

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Osteoclasts
Bone Resorption
Osteopetrosis
Fatty Acids
Macrophages
Inflammation
Innate Immunity
Lactic Acid
Macrophage Activation
Bone Remodeling
Glycolysis
Nervous System Diseases
Reactive Oxygen Species
Mitochondria
Homeostasis
Liver

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Mitochondrial complex i activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. / Jin, Zixue; Wei, Wei; Yang, Marie; Du, Yang; Wan, Yihong.

In: Cell Metabolism, Vol. 20, No. 3, 02.09.2014, p. 483-498.

Research output: Contribution to journalArticle

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