Figure 1: Mitochondrial-derived vesicles regulate multiple routes of the innate immune response. Following local damage of mitochondrial proteins and lipids in response to oxidative stress, mitochondrial-derived vesicles (MDVs) form and transport damaged cargo to the lysosome for degradation. These MDVs can either be single membrane vesicles derived exclusively from the outer membrane or double membrane vesicles carrying inner membrane or matrix-derived cargoes. PINK1 and Parkin are required for the formation of inner membrane-derived MDVs, while Parkin is required for the trafficking of outer membrane-derived MDVs to the lysosome. Tollip is essential for coordinating the trafficking of these Parkin-dependent outer membrane derived MDVs to the lysosome. Once in the lysosome, it is thought these broken down mitochondrial antigens can be further processed by the proteasome and loaded onto MHC I molecules in the endoplasmic reticulum (ER) prior to presentation at the plasma membrane. Damage to the mitochondria can additionally result in the release of mitochondrial DNA, stimulating the STING-mediated type I Interferon immune response. STING resides in the ER and following mitochondrial DNA activation, moves to the Golgi to activate IRF3 nuclear translocation and subsequently influences pro-inflammatory gene expression. Stimulator of Interferon Genes (STING) activation also stimulates nuclear factor κB (NFκB) mediated pro-inflammatory gene expression. The presence of Parkin and its role in mitoQC aids in the suppression of STING-mediated inflammation. In comparison, Tollip is a negative regulator of NFκB downstream of interleukin-1β (IL-1β) mediated Toll-like receptor (TLR) activation. Tollip additionally interacts and stabilizes STING expression to maintain the type I Interferon immune response. However, following mitochondrial stress, Tollip may be sequestered away from STING, resulting in a dampening of the innate immune response. IRAK: Interleukin-1 receptor associated kinase; IRF3: interferon regulatory factor 3; mtDNA: mitochondrial DNA; PINK1: PTEN induced putative kinase 1; Tollip: Toll-interacting protein.