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Mitochondrial dysfunction induce immunoproteasome and MHC class I responses in lung aging

Aging has emerged as the single greatest risk factor for pulmonary disease. Mitochondrial dysfunction is a driving pathomechanism of age-related chronic lung diseases. Imbalanced proteostasis and altered immune function have also been identified as age-related pathogenetic drivers of lung disease. We here explore how mitochondrial dysfunction in a premature aging model affects the proteasome and proteasome-related immune responses. Specifically, we investigate metabolic regulation of the immunoproteasome, a specialized type of proteasome involved in MHC class I antigen presentation. In aged mouse lungs, proteomic analysis revealed an age-related signature of mitochondrial dysfunction with reduced expression of proteins involved in oxidative phosphorylation but prominent induction of the immunoproteasome and MHC class I related immune responses pathway. Using cells from a premature aging mouse model, i.e. the mutator mice that show severely impaired mitochondrial metabolism due to the expression of a defective mitochondrial DNA polymerase, we observed concerted upregulation of the immunoproteasome and the MHC I antigen presentation pathway, which was driven by activation of STAT1 via the cGAS/Sting DNA sensors as shown by knockdown of cGAS. Importantly, the mutator was able to activate CD8+ T-lymphocytes via immunoproteasome-dependent MHC class I antigen presentation. Activation was suppressed by cGAS silencing or inhibition of immunoproteasome activity. In conclusion, our findings demonstrate that dysfunctional mitochondria induce the immunoproteasome and MHC I antigen presentation adaptive immune responses. In the aging lung defective mitochondrial function might thereby contribute to autoimmunity via altered MHC I antigen presentation and autoreactive T cell activity.