Mitochondria-induced immune response as a trigger for neurodegeneration : A pathogen from within

Funding: This work was supported by a Juan de la Cierva grant (IJC2018-036938-I). A.Q. received funds from the European Research Council (Starting grant NEUROMITO, ERC-2014-StG-638106), MINECO Proyectos I + D de Excelencia (SAF2014-57981P; SAF2017-88108-R), AGAUR (2017SGR- 323), and "la Caixa" Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400018. This work was supported by a Juan de la Cierva grant (IJC2018?036938?I). A.Q. received funds from the European Research Council (Starting grant NEUROMITO, ERC?2014?StG?638106), MINECO Proyectos I + D de Excelencia (SAF2014?57981P; SAF2017?88108?R), AGAUR (2017SGR? 323), and ?la Caixa? Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400018. Altres ajuts: NEUROMITO Altres ajuts: "la Caixa" Foundation Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.