Fig. 1.

Innate immunity activation due to mutations in mitochondrial factors is mediated in the cytosol via the cGAS/STING pathway (when accumulated and possibly fragmented mtDNA is extruded to the cytosol) or the DDX58/IFIH1/MAVS sensors in the pattern recognition RLR pathway (when accumulated mitochondrial double-strand RNA is extruded). They stimulate the nuclear induction of interferon type I signaling. It is unclear if these established mechanisms also are prominent in ClpP-deficient cells, or additional pattern recognition receptors (TLR, NLR) and other cytosolic sensors play a relevant role. MRG, mitochondrial ribosomal granule; VDAC, PORIN; DDX58, RIG-I; IFIH1, MDA-5; STING, STING1, also known as TMEM173; ISRE, interferon-stimulated response element in the promoter of nuclear genes; other symbols can be retrieved in the GeneCards database