PMID- 31063702
OWN - NLM
STAT- MEDLINE
DCOM- 20200601
LR  - 20240214
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 33
IP  - 8
DP  - 2019 Aug
TI  - Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast 
      formation in macrophages.
PG  - 9167-9181
LID - 10.1096/fj.201900010RR [doi]
AB  - The mitochondria-to-nucleus retrograde signaling (MtRS) pathway aids in cellular 
      adaptation to stress. We earlier reported that the Ca(2+)- 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-kappaB, NFAT2, and C/EBPdelta 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.
FAU - Angireddy, Rajesh
AU  - Angireddy R
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Kazmi, Hasan Raza
AU  - Kazmi HR
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Srinivasan, Satish
AU  - Srinivasan S
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Sun, Li
AU  - Sun L
AD  - The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at 
      Mount Sinai, New York, New York, USA.
FAU - Iqbal, Jameel
AU  - Iqbal J
AD  - The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at 
      Mount Sinai, New York, New York, USA.
FAU - Fuchs, Serge Y
AU  - Fuchs SY
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Guha, Manti
AU  - Guha M
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Kijima, Takashi
AU  - Kijima T
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Yuen, Tony
AU  - Yuen T
AD  - The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at 
      Mount Sinai, New York, New York, USA.
FAU - Zaidi, Mone
AU  - Zaidi M
AD  - The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at 
      Mount Sinai, New York, New York, USA.
FAU - Avadhani, Narayan G
AU  - Avadhani NG
AD  - Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA.
LA  - eng
GR  - P01 CA165997/CA/NCI NIH HHS/United States
GR  - R01 CA092900/CA/NCI NIH HHS/United States
GR  - R01 DK113627/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190507
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Membrane Proteins)
RN  - 0 (Mpv17 protein, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Cell Differentiation
MH  - Electron Transport Complex IV/antagonists & inhibitors/genetics/*metabolism
MH  - Gene Knockdown Techniques
MH  - Macrophages/classification/*cytology/*physiology
MH  - Membrane Proteins/deficiency/genetics
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Mitochondria/metabolism
MH  - Osteoclasts/*cytology/*physiology
MH  - Osteogenesis
MH  - Phagocytosis/*physiology
MH  - RAW 264.7 Cells
MH  - RNA, Small Interfering/genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - Stress, Physiological
PMC - PMC6662975
OTO - NOTNLM
OT  - Subunit IVi1
OT  - inflammatory cytokines
OT  - reactive oxygen species
OT  - respiratory changes
OT  - retrograde signaling
COIS- The authors acknowledge the technical help of Maura Sheehan and Liam Piscetelli 
      (Department of Biomedical Sciences, School of Veterinary Medicine, University of 
      Pennsylvania, Philadelphia, PA). The authors acknowledge Dr. Pavan from Dr. Anna 
      Kashina's laboratory for helping with live cell imaging (both from Department of 
      Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania). 
      The authors also acknowledge the help of Dr. Gordon Ruthel (Department of 
      Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania) 
      and the PENN Vet imaging core (University of Pennsylvania School of Veterinary 
      Medicine) in confocal imaging. This work was supported in part by the U.S. 
      National Institutes of Health (NIH) National Institutes of Arthritis and 
      Musculoskeletal and Skin Diseases Grants R01AR06066 (to M.Z. and N.G.A) and 
      R01AR6592 (to M.Z.), NIH National Institute of Diabetes and Digestive and Kidney 
      Diseases Grant R01DK113627 (to M.Z.), as well as the Harrington Discovery 
      Institute. N.G.A. also acknowledges an endowment from the Harriet Ellison 
      Woodward foundation. The authors declare no conflicts of interest.
EDAT- 2019/05/08 06:00
MHDA- 2020/06/02 06:00
PMCR- 2020/05/07
CRDT- 2019/05/08 06:00
PHST- 2019/05/08 06:00 [pubmed]
PHST- 2020/06/02 06:00 [medline]
PHST- 2019/05/08 06:00 [entrez]
PHST- 2020/05/07 00:00 [pmc-release]
AID - FJ_201900010RR [pii]
AID - 10.1096/fj.201900010RR [doi]
PST - ppublish
SO  - FASEB J. 2019 Aug;33(8):9167-9181. doi: 10.1096/fj.201900010RR. Epub 2019 May 7.