Abstract

Aging is strongly associated with pulmonary disorders. Mitochondrial dysfunction is a hallmark of aging and a driving pathomechanism of age-related lung diseases. Mitochondrial stress and released mtDNA has been shown to activate innate immune responses via DNA sensing. However, whether mitochondrial stress also regulates adaptive immune responses such as MHC I antigen presentation has not been investigated so far. We here investigated regulation of MHC I antigen presentation by mitochondrial stress using proteomic analysis of aged mouse lungs and an in vitro model of chronic mitochondrial dysfunction.

Proteomic analysis of young versus aged mouse lungs revealed an age-related signature of mitochondrial dysfunction with reduced expression of proteins involved in oxidative phosphorylation but prominent induction of the MHC I antigen presentation pathway. In cells derived from the mutator mouse model, which represents a system of premature aging, disturbed mitochondrial function resulted in a concerted upregulation of the MHC I antigen presentation pathway as demonstrated by proteomic and FACS analysis. Importantly, expression and activity of the immunoproteasome (IP), a specialized type of proteasome involved in the generation of antigenic MHC I peptides was strongly upregulated compared to controls. Induction was driven by activation of STAT1 via cGAS/STING DNA sensors as shown by silencing experiments.

In conclusion, our findings show that dysfunctional mitochondria induce stress signaling to activate IP function and MHC I antigen presentation. In the aging lung defective mitochondrial function might thereby contribute to autoimmunity via altered MHC class I antigen presentation.