ORIGINAL ARTICLES

Termination of damaged protein repair defines the occurrence of symptoms in carriers of the m.3243A>G tRNA^Leu mutation

R G E van Eijsden^1,2,3, L M T Eijssen^4,5, P J Lindsey⁴, C M M van den Burg⁴, L E A de Wit⁶, M E Rubio-Gozalbo⁷, C E M de Die⁸, T Ayoubi^4,9, W Sluiter⁶, I F M de Coo¹⁰, H J M Smeets^1,2,4

¹ Department of Genetics and Cell Biology, Clinical Genetics, Maastricht University, Maastricht, The Netherlands
² Research Institute Growth & Development, Maastricht University, Maastricht, The Netherlands
³ MicroArray Facility, VIB, Leuven, Belgium
⁴ Department of Genetics and Cell Biology, Clinical Genomics, Maastricht University, Maastricht, The Netherlands
⁵ BiGCaT Bioinformatics, Maastricht University, Maastricht, The Netherlands
⁶ Department of Biochemistry, Mitochondrial Research Unit, Erasmus MC, Rotterdam, The Netherlands
⁷ Department of Paediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Hospital, Maastricht, The Netherlands
⁸ Department of Clinical Genetics, Maastricht University Hospital, Maastricht, The Netherlands
⁹ Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
¹⁰ Department of Neurology, Erasmus MC, Rotterdam, The Netherlands

Dr H J M Smeets, Maastricht University, Department of Genetics and Cell Biology, PO Box 616 (post-box 16), 6200 MD Maastricht, The Netherlands; Bert.Smeets{at}Molcelb.Unimaas.nl

Background: 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.

Methods: 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.

Results and conclusions: Gene expression changes were relatively subtle. In the asymptomatic group 200 transcripts were upregulated and 12 were downregulated, whereas in the symptomatic group 15 transcripts were upregulated and 52 were downregulated. In the asymptomatic 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 upregulated 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 asymptomatic 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.

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