The m.3243A>G mutation in the mitochondrial tRNA(Leu)(UUR) gene is an example of a mutation causing a very heterogeneous phenotype. It is the most frequent cause (80%) of the MELAS syndrome (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes), but it can also lead in addition or separately to type 2 diabetes, deafness, renal tubulopathy and/or cardiomyopathy. To identify pathogenic processes induced by this mutation, we compared global gene expression levels of muscle biopsies from affected and unaffected mutation carriers with controls. Gene expression changes were relatively subtle. In the a symptomatic group 200 transcripts were up- and 12 were down-regulated, whereas in the symptomatic groups this was 15 and 52 respectively. In the a symptomatic group, oxidative phosphorylation (OXPHOS) complex I and IV genes were induced. Protein turnover and apoptosis were elevated, most likely due to the formation of dysfunctional and reactive oxygen species (ROS) damaged proteins. These processes returned to normal in symptomatic patients. Components of the complement system were up-regulated in both groups, but the strongest in the symptomatic group, which might indicate muscle regeneration. Most likely protein damage and OXPHOS dysfunction stimulate repair (protein regeneration) and metabolic adaptation (OXPHOS). In a symptomatic individuals these processes suffice to prevent the occurrence of symptoms. However, in affected individuals the repair process terminates, presumably because of excessive damage, and switches to muscle regeneration, as indicated by a stronger complement activation. This switch leaves increasingly damaged tissue in place and muscle pathology becomes manifest. Therefore, the expression of complement components might be a marker for the severity and progression of MELAS clinical course.
van Eijsden, R., Eijssen, L. M., Lindsey, P., van den Burg, C., de Wit, E., Rubio-Gozalbo, M. E., de Die-Smulders, C. E. M., Ayoubi, T., Sluiter, W., de Coo, I., & Smeets, H. (2008). Termination of damaged protein repair defines the occurrence of symptoms in carriers of the m.3243A > G tRNA(Leu) mutation. Journal of Medical Genetics, 45(8), 525-534. https://doi.org/10.1136/jmg.2008.057497