Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is primarily caused by the heteroplasmic m.3243A>G/MT-TL1 pathogenic variant. Patients exhibit elevated circulating cell-free mtDNA (cf-mtDNA) in plasma, which acts as a damage-associated molecular pattern. Using patient-derived fibroblasts and neuronal progenitors, as well as transmitochondrial cytoplasmic hybrids (cybrids), we show that mutant cells release higher levels of cf-mtDNA than wild-type controls, demonstrating that the m.3243A>G pathogenic variant drives mtDNA release. Mechanistically, increased mitochondrial oxidative stress promotes mtDNA oxidation and fragmentation, leading to Ca2+ overload and subsequent mtDNA extrusion. This, in turn, triggers inflammasome activation and pyroptosis, resulting in the secretion of pro-inflammatory cytokines and the activation of innate immune pathways. Pharmacological inhibition of the Mitochondrial Calcium Uniporter (MCU) or Voltage-Dependent Anion Channel (VDAC) reduced mtDNA release, confirming their involvement. Overall, our findings reveal a previously unrecognized mechanism in MELAS linking mitochondrial dysfunction to innate immune activation, with potential implications for therapeutic intervention.
Moresco, M., Rapone, A., Tropeano, C. V., Capristo, M., Capirossi, G., Ormanbekova, D., Fiorini, C., Pasti, A. P., Valle, F., Danese, A., Patergnani, S., Caporali, L., La Morgia, C., Suomalainen, A., Pinton, P., Tigano, M., Carelli, V., Maresca, A.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 15
- Comments 0