Mitochondrial proteases CLPXP, LONP1, and OMA1 critically regulate inflammation and immunity

The global rise in chronic inflammatory and autoimmune disorders has intensified research into cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Current therapeutic strategies often fall short, highlighting the need for novel targets. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses, yet their specific roles in immunometabolism and as therapeutic targets remain underexplored. This review addresses this critical gap by synthesizing current knowledge on these vital regulators.

This comprehensive review synthesized current knowledge on the role of specific mitochondrial proteases—CLPXP, LONP1, i-AAA, m-AAA, and OMA1—in immune cells and various inflammatory pathologies. The authors explored the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating findings from both immune and non-immune cell types, including those involved in cancer, neurodegeneration, and renal injury. They examined their function as context-dependent regulators of immunometabolic signaling, considering effects shaped by cell type, metabolic state, and stress conditions. The review also discussed emerging small molecules and drugs targeting these proteases, highlighting their potential therapeutic role.

Mitochondrial proteases are not merely housekeeping enzymes but active modulators of immune and inflammatory responses. CLPXP and LONP1 are critical for selectively degrading misfolded or damaged proteins, thereby maintaining mitochondrial function and preventing the release of mitochondrial-derived danger signals (DAMPs). Dysregulation of these proteases directly impacts mitochondrial stress pathways and reactive oxygen species (ROS) production, which are central to immune cell activation and inflammatory cascades. This review highlights how proteases like OMA1 influence mitochondrial dynamics (fission/fusion) and apoptosis, thereby modulating the inflammatory fate of cells. The authors found that altered activity of i-AAA and m-AAA proteases contributes to the pathogenesis of various inflammatory diseases by affecting mitochondrial integrity and subsequent immune cell responses. Their function is highly context-dependent, varying with cell type and metabolic state, suggesting complex regulatory roles in immunometabolism.