Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention.

Abstract

SIGNIFICANCE In the case of heterogeneous autoimmune diseases (AIDs), the efficacy of single-pathway immunosuppression is limited, the toxicity is substantial, and the problem of cell type-specific metabolic vulnerability cannot be addressed. MECHANISM New evidence highlights mitochondrial quality control (MQC) as an important regulatory axis of the immune set point. MQC is a coordinated network involving mitochondrial biogenesis, dynamics, mitophagy, proteostasis, protein import machinery, and selective removal of damaged mitochondrial components, including mitochondria-derived vesicles. Dysregulation across these interconnected MQC modules may contribute to key pathological events: impaired biogenesis compromises the metabolic fitness of regulatory T cells; an altered fission-fusion balance can influence macrophage inflammatory polarization; and defective mitophagy may increase the accumulation or release of immunostimulatory mitochondrial components, including mitochondrial DNA (mtDNA), triggering cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING)-driven type I interferon (IFN-I) amplification and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome hyperactivation. In parallel, impaired mitochondrial proteostasis, defective mitochondrial protein import machinery, dysregulated mitochondrial unfolded protein response (UPRmt) signaling, and altered Mitochondrial-derived vesicle (MDV)-mediated cargo disposal may further shape mitochondrial stress and immune-cell function. INNOVATION We propose a conceptual shift from blanket immunosuppression to potential precision metabolic-immune reprogramming. This framework proposes that accessible MQC-related readouts, including transcription factor A (TFAM), Dynamin-related protein1 (Drp1) phosphorylation patterns, and Microtubule-associated protein 1A/1B-light chain 3 (LC3), may help inform treatment timing and therapeutic windows in future translational studies. FUTURE DIRECTIONS To advance potential medicine in AIDs, prospective clinical studies should evaluate whether MQC-related biomarkers can identify treatment-responsive subgroups. For example, future studies should assess whether disease-stage and cell-specific modulation of mitophagy or mitochondrial dynamics improves treatment responses in rheumatoid arthritis (RA) patients stratified according to synovial Translocase of Outer Mitochondrial Membrane 7 (TOMM7) expression and metabolic state. These studies should test whether fission inhibition, restoration of regulated fission, or normalization of dysregulated fusion is beneficial in specific patient subgroups.