Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism

Area of Science:

• Cell Biology
• Immunology
• Mitochondrial Biology

Background:

• Lysosomal damage, from pathogens or silica, releases proteases into the cytosol.
• The impact of this limited lysosomal content leakage on cytoplasmic organelles, particularly mitochondria, remains unclear.

Purpose of the Study:

• To investigate if lysosomal damage affects mitochondrial proteome and function in macrophages.
• To elucidate the mechanism of mitochondrial metabolic reprogramming following lysosomal damage.

Main Methods:

• Utilized in vitro cell models and an in vivo mouse model of endomembrane damage.
• Employed techniques including protease activity assays, mitochondrial function assessments, single-cell RNA-sequencing, and drug modulation of macrophage metabolism.

Main Results:

• Lysosomal damage triggers cell death-independent proteolytic remodeling of the mitochondrial proteome in macrophages.
• Mitochondrial metabolic reprogramming necessitates lysosomal cathepsin leakage and is independent of mitophagy, mitoproteases, and proteasome.
• In vivo, macrophages with internalized crystals showed impaired mitochondrial function, and lysosomal damage skewed macrophage metabolic and immune responses.

Conclusions:

• Uncovered a novel inter-organelle communication pathway linking lysosomal damage to mitochondrial metabolic reprogramming in macrophages.
• Demonstrated that modulating macrophage metabolism affects host responses to Mycobacterium tuberculosis infection in an endomembrane damage-dependent manner.