Immune Surveillance of Mitochondrial DNA Deletions?

Regular readers will know that mitochondrial DNA damage is thought to be an important contributing cause of aging. It can lead to dysfunctional mitochondria that overtake cells and turn them into exporters of damaging reactive compounds, harming both surrounding tissues and important proteins that circulate widely in the body.

This is a fascinating paper that suggests the immune system has evolved to detect the presence of mitochondrial DNA deletions and destroy the cells that harbor those damaged mitochondria. Assuming this holds up there are several ways one could interpret this mechanism: firstly that mitochondrial DNA damage is less important than thought because there are more processes controlling it; or secondly that it is more important because it will lead to increased inflammation and immune system activation, which is a serious issue in later life; and either way thirdly that the age-related decline of the immune system should be considered more important because here is yet another fundamental aspect of aging that it influences.

Mutations in mitochondrial (mt) DNA accumulate with age and can result in the generation of neopeptides. Immune surveillance of such neopeptides may allow suboptimal mitochondria to be eliminated, thereby avoiding mt-related diseases, but may also contribute to autoimmunity in susceptible individuals. To date, the direct recognition of neo-mtpeptides by the adaptive immune system has not been demonstrated.

In this study we used bioinformatics approaches to predict major histocompatibility complex binding of neopeptides identified from known deletions in mtDNA. Six such peptides were confirmed experimentally to bind to HLA-A*02. Pre-existing human CD4+ and CD8+ T cells from healthy donors were shown to recognize and respond to these neopeptides. One remarkably promiscuous immunodominant peptide (P9) could be presented by diverse MHC molecules to CD4+ and/or CD8+ T cells from 75% of the healthy donors tested.

The common soil microbe, Bacillus pumilus, encodes a 9-mer that differs by one amino acid from P9. Similarly, the ATP synthase F0 subunit 6 from normal human mitochondria encodes a 9-mer with a single amino acid difference from P9 with 89% homology to P9. T cells expanded from human peripheral blood mononuclear cells using the B. pumilus or self-mt peptide bound to P9/HLA-A2 tetramers, arguing for cross-reactivity between T cells with specificity for self and foreign homologs of the altered mt peptide.

These findings provide proof of principal that the immune system can recognize peptides arising from spontaneous somatic mutations and that such responses might be primed by foreign peptides and/or be cross-reactive with self.

Looking back in the Fight Aging! archives, I see a paper from a couple of years ago in which researchers link inflammation in aging with mitochondrial damage, but via the mechanism of reactive oxygen species production. That seems worth another look in light of the above recent research.



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