Mitochondrial DNA as inflammatory DAMP: a warning of an aging immune system?

Senescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed ‘inflammaging', with increased levels of proinflammatory cytokines, both at the tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA — the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP–AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging.