Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages

FASEB J. 2019 Aug;33(8):9167-9181. doi: 10.1096/fj.201900010RR. Epub 2019 May 7.


The mitochondria-to-nucleus retrograde signaling (MtRS) pathway aids in cellular adaptation to stress. We earlier reported that the Ca2+- and calcineurin-dependent MtRS induces macrophage differentiation to bone-resorbing osteoclasts. However, mechanisms through which macrophages sense and respond to cellular stress remain unclear. Here, we induced mitochondrial stress in macrophages by knockdown (KD) of subunits IVi1 or Vb of cytochrome c oxidase (CcO). Whereas both IVi1 and Vb KD impair CcO activity, IVi1 KD cells produced higher levels of cellular and mitochondrial reactive oxygen species with increased glycolysis. Additionally, IVi1 KD induced the activation of MtRS factors NF-κB, NFAT2, and C/EBPδ as well as inflammatory cytokines, NOS 2, increased phagocytic activity, and a greater osteoclast differentiation potential at suboptimal RANK-L concentrations. The osteoclastogenesis in IVi1 KD cells was reversed fully with an IL-6 inhibitor LMT-28, whereas there was minimal rescue of the enhanced phagocytosis in these cells. In agreement with our findings in cultured macrophages, primary bone marrow-derived macrophages from MPV17-/- mice, a model for mitochondrial dysfunction, also showed higher propensity for osteoclast formation. This is the first report showing that CcO dysfunction affects inflammatory pathways, phagocytic function, and osteoclastogenesis.-Angireddy, R., Kazmi, H. R., Srinivasan, S., Sun, L., Iqbal, J., Fuchs, S. Y., Guha, M., Kijima, T., Yuen, T., Zaidi, M., Avadhani, N. G. Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages.

Keywords: Subunit IVi1; inflammatory cytokines; reactive oxygen species; respiratory changes; retrograde signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Gene Knockdown Techniques
  • Macrophages / classification
  • Macrophages / cytology*
  • Macrophages / physiology*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mitochondria / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / physiology*
  • Osteogenesis
  • Phagocytosis / physiology*
  • RAW 264.7 Cells
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Stress, Physiological


  • Membrane Proteins
  • Mpv17 protein, mouse
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Electron Transport Complex IV