fig1

Figure 1. Mitochondrial dysfunction in systemic lupus erythematosus (SLE). In SLE, mitochondrial respiration is impaired, with a shift of the ratio between adenosine triphosphate (ATP) and reactive oxidative species (ROS) production, with accumulation of the latter. Given the proximity between the respiratory chain complex and mitochondrial nucleic acids, mtDNA has been proved to be particularly susceptible to oxidative damage. Oxidized mtDNA, in turn, can be recognized as a damage-associated molecular pattern, and trigger type I interferon (IFN) production through activation of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING and of toll-like receptor 9 (TLR9). Additionally, in SLE monocytes, mtRNA was shown to activate RIG-like receptors (RLRs), induce the production of interleukin-1beta (IL-1β) and activate inflammasome, thus contributing to another pro-inflammatory pathway. Healthy cells are usually able to promptly deal with dysfunctional mitochondria, either by ejecting oxidized mtDNA into nucleoids redirected to lysosomes for degradation, or by recycling mitochondria through mitophagy. However, those mechanisms seem to be defective in SLE. Further, in SLE, the anti-inflammatory mitokine growth differentiation factor 15 (GDF 15), despite increased production, is not enough to put a brake into the inflammatory milieu. Similarly, the anti-inflammatory metabolite itaconate, which acts by reducing mitochondrial antiviral signaling protein (MAVS) oligomerization, seems to be reduced in SLE. As a consequence, increased MAVS oligomers become available as adaptors for the sensors melanoma differentiation-associated protein 5 (MDA-5) and retinoic acid-inducible gene 1 (RIG-1), themselves key to IFN production. Figure created in BioRender.com.