The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome

摘要: Mitochondrial dysfunction activates mitochondria-to-nucleus signaling pathways whose components are mostly unknown. Identification of these is important to understand the molecular mechanisms underlying mitochondrial diseases and discover putative therapeutic targets. MELAS syndrome a rare neurodegenerative disease caused by mutations in (mt) DNA affecting mt-tRNA(Leu(UUR)). Patient cybrid cells exhibit elevated oxidative stress. Moreover, mutant mt-tRNAs(Leu(UUR)) lack taurine-containing modification normally present at wobble uridine (U34) wild-type mt-tRNA(Leu(UUR)), which considered an etiology MELAS. However, mechanism still unclear. We found that cybrids significant decrease steady-state levels several mt-tRNA-modification enzymes, not due transcriptional regulation. demonstrated stress mediates NFkB-dependent induction microRNA-9/9*, acts as post-transcriptional negative regulator enzymes GTPBP3, MTO1 TRMU. Down-regulation microRNA-9/9* affects U34 status non-mutant tRNAs contributes phenotype. Anti-microRNA-9 treatments reverse phenotype, whereas miR-9 transfection mimics effects siRNA-mediated down-regulation Our data represent first evidence mt-DNA can directly affect microRNA expression. we demonstrate mt-tRNAs dynamic respond modulating expression mt-tRNA-modifying enzymes. crucial player it regulates nuclear genes response changes functional state mitochondria.