Figure 1.

Interconnection between the MAPK pathway, mitophagy and CXCL10 expression. Blocking the KRAS oncogenic pathway with MAP2K/MEK inhibitors allows for the removal of chemo-induced mitophagy inhibition at different stages. First, phagophore formation is facilitated by loss of ULK1 inhibition and thus its increased phosphorylation on serine 555. Second, by restoring gene and protein expression of OPTN (optineurin), chemotherapy-damaged mitochondria can be more easily engulfed in phagophores. Phosphorylation of TBK1 on serine 172 also promotes activation of OPTN at ubiquitin (U) chains on the surface of mitochondria. Through the degradation of these in amphisomes or autolysosome-like structures, mitochondrial DNA activates TLR9, which in turn allows the expression of CXCL10 and the recruitment of CD8⁺ T cells.