Innate immunity and tolerance toward mitochondria

Abstract

Mitochondria are intracellular organelles that originate from a bacterial symbiont, and they retain multiple features of this bacterial ancestry. The immune system evolved to detect the presence of invading pathogens, including bacteria, to eliminate them by a diversity of antimicrobial mechanisms and to mount long-term protective immunity. Due to their bacterial ancestry, mitochondria are sensed by the innate immune system, and trigger inflammatory responses comparable to those induced by pathogenic bacteria. In both cases, innate sensing mechanisms involve Toll-Like Receptors, Formyl Peptide Receptors, inflammasomes or the cGAS/STING pathway. Stressed mitochondria release mitochondrial molecules, such as cardiolipin and mitochondrial DNA, which are sensed as cellular damage potentially caused by infections. Recent research has identified several conditions in which mitochondrial stress-induced immunity is essential to effective antimicrobial defenses. But, in pathological conditions, the abnormal activation of the innate immune system by damaged mitochondria results in auto-inflammatory or autoimmune diseases. To prevent undesirable mitochondria-targeted responses, immune tolerance toward mitochondria must be established, involving regulation of mitophagy and mitochondrial permeability, as well as activation of specific nucleases and pro-apoptotic caspases. Overall, recent findings identify mitochondria as central in the induction of innate immunity, and provide new insights as to how immune responses to these multi-functional organelles might be exploited therapeutically in various disease states.