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

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Immunology

Background:

• Mitochondria-to-nucleus retrograde signaling (MtRS) facilitates cellular adaptation to stress.
• Previous work linked MtRS to macrophage differentiation into osteoclasts.
• Mechanisms of macrophage stress sensing and response remain incompletely understood.

Purpose of the Study:

• To investigate how macrophages sense and respond to mitochondrial stress.
• To determine the role of cytochrome c oxidase (CcO) dysfunction in macrophage inflammatory and functional responses.
• To elucidate the impact of CcO dysfunction on osteoclastogenesis.

Main Methods:

• Induced mitochondrial stress in macrophages via knockdown of CcO subunits (IVi1 or Vb).
• Assessed reactive oxygen species (ROS) levels, glycolysis, inflammatory pathway activation (NF-κB, NFAT2, C/EBPδ), cytokine production, NOS 2 expression, and phagocytic activity.
• Evaluated osteoclast differentiation potential and effects of IL-6 inhibition.
• Utilized MPV17-/- mice as a model for mitochondrial dysfunction.

Main Results:

• IVi1 knockdown increased cellular/mitochondrial ROS and glycolysis.
• IVi1 knockdown activated MtRS factors, inflammatory cytokines, NOS 2, and enhanced phagocytosis.
• IVi1 knockdown significantly increased osteoclast differentiation, reversible with IL-6 inhibition.
• Macrophages from MPV17-/- mice exhibited increased osteoclast formation propensity.

Conclusions:

• Cytochrome c oxidase (CcO) dysfunction impairs mitochondrial function and triggers inflammatory signaling in macrophages.
• CcO dysfunction enhances macrophage phagocytic capacity and promotes osteoclastogenesis.
• This study reveals a novel link between mitochondrial dysfunction, inflammation, and bone metabolism via macrophage regulation.