Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within

Abstract

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.

Keywords: antiviral response; inflammation; innate immunity; interferon; mitochondrial disorders; mitochondrial dysfunction; mtDNA; mtRNA; neurodegeneration.

Figure 1

mtDNA-activated immune pathways. Under mitochondrial insults (oxidative stress, infections, etc.) or mitochondrial quality control impairment, mtDNA is released to the cytosol where it engages different receptors, activating inflammatory and innate immune signaling pathways. From the left: Oxidized mtDNA stimulates inflammasome activity leading to caspase-1-mediated maturation of pro-inflammatory IL-1β and IL18; mtDNA activates the cGAS–STING pathway triggering interferon response via IRF3 and NF-κB; TLR9 recognizes mtDNA, resulting in activation of NF-κB or MAPK and pro-inflammatory cytokines production. mtDNA also promotes non-apoptotic cell death trough TLR9/IFN-β signaling. Genotoxic stress and DNA repair response are also mediated by cytosolic mtDNA.

Figure 2

Proposed mechanisms of mtDNA release to the cytosol: (A) Under extreme stress conditions, activation of BAX/BAK leads to MOMP. Following MOMP, the outer membrane pores progressively widen, allowing for the extrusion of inner mitochondrial membrane into the cytosol and its permeabilization to release mitochondrial nucleic acids. (B) Under mild-stress conditions, VDAC oligomer pores promote MOMP and thus make mtDNA release into the cytosol possible. (C) mPTP opening allows the release of small mtDNA fragment. Abbreviations: MOMP: mitochondrial outer membrane permeabilization; MIMP: mitochondrial inner membrane permeabilization; MPTP: mitochondrial permeability transition pore; CsA: cyclosporine A.

Figure 3

mtdsRNA-activated immune pathways. Dysfunctional mitochondria can accumulate mtdsRNA intermediates, either as a consequence of mitochondrial defects or due to external stimuli. Once released into the cytosol, mtdsRNA binds to the immune sensors MDA5 and RIG1, eliciting interferon type I response via MAVS. mtdsRNA can also bind and activate the antiviral kinase PKR, leading to phosphorylation of eIF2α and inhibition of global translation or cell death under sustained PKR activation.

Figure 4

Mitochondrial nucleic acids-driven inflammation as a critical regulator of disease progression in neurodegenerative processes. Dysregulation of mitochondrial function leads to the activation of type I IFN signaling by mt-derived nucleic acids. The activation and the propagation of the inflammatory response may contribute to secondary damage and neurodegeneration. Besides mitochondrial dysfunction promoting inflammation, inflammation per se can lead to mitochondrial dysfunction, suggesting the existence of a pro-inflammatory loop with mitochondria as a central player.