Abstract
Dilated cardiomyopathy (DCM) is a serious public health problem that increases the risk of developing heart failure. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial tRNA (mt-tRNA) mutations plays a putative role in the pathogenesis of this disease, despite its pathophysiology remaining poorly understood. In this study, a novel 12265A>G mutation in mt-tRNA(Ser(AGY)) was identified from a Chinese pedigree with maternally inherited DCM, together with a known mt-tRNA(Cys) 5821G>A mutation. Interestingly, the novel m.12265A>G mutation changed the well-conserved adenosine at Position 73 (A73) to guanine (G73) at the 3'-end of the mt-tRNA(Ser(AGY)) acceptor arm, while the G-to-A transition at 5821 occurred at the acceptor arm of mt-tRNA(Cys), disrupting conserved base pairing (G6-C67). Transmitochondrial cybrid-based study demonstrated that cell lines with m.12265A>G and m.5821G>A mutations showed impaired mitochondrial functions, including significant reductions in mitochondrial ATP, membrane potential, NAD(+)/NADH ratio, mitochondrial DNA (mtDNA) content, mitochondrial transcription factor A (TFAM) mRNA expression levels, and respiratory chain enzyme Complex I and III activities, whereas the levels of reactive oxygen species (ROS), calcium ions (Ca(2+)), and lactate were enhanced in mutant cells compared to controls (p < 0.05). Thus, the m.12265A>G and m.5821G>A mutations may affect mt-tRNA metabolism and impair mitochondrial function, which is involved in DCM. Taken together, our study broadens the genotypic interpretation of mt-tRNA mutations linked to disease.