Abstract
Several inherited human diseases have been linked to mitochondrial aminoacyl-tRNA synthetases (mtARSs). Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a leukodystrophy caused by mutations in the DARS2 gene which encodes mitochondrial aspartyl-tRNA synthetase. As mitochondrial ARSs are key components of the mitochondrial translation apparatus, we investigated the effects of DARS2 mutations on mitochondrial functions and mitochondrial morphology in an LBSL patient. In fibroblasts from the patient with LBSL, biosynthesis of respiratory chain complex proteins encoded by mitochondrial DNA was decreased, while those encoded by nuclear DNA were not. Cellular oxygen consumption rates and respiratory control ratio were decreased in the LBSL patient; in addition, fragmentation of mitochondria was increased, while their tubular elongation and interconnectivity were decreased. Taken together, these findings suggest that DARS2 mutations impair translations of mitochondrial DNA-encoded respiratory chain complex proteins, consequently causing dysfunction of cellular respiration and impediment of mitochondrial dynamics, which highlights the role of mtARSs in the maintenance of normal mitochondrial bioenergetics and dynamics.
Highlights
We investigated the effects of DARS2 mutations on the mitochondrial functions involved in the biosynthesis of respiratory chain (RC) complex components and cellular respiratory function in LBSL
Nuclear-encoded RC complex proteins, including NDUFA9 and COX IV, did not demonstrate significant differences between the LBSL and normal fibroblasts. This disparity in synthesis of mtDNAencoded and nuclear-encoded RC complex proteins was similar to those presented by the fibroblasts from Myoclonic epilepsy with ragged-red fibers (MERRF) patient, in which levels of ND5 (0.68±0.11%) and COXII (0.43±0.03%) were decreased, while NDUFA9 and COX IV levels were not significantly changed, when compared to normal controls
Because both of the DARS2 mutations harbored by the LBSL patient in this study result in loss of an entire exon in mRNA transcripts, significant alterations to the structure and function of the synthetic aspartyl-transfer RNA (tRNA) synthetase could be expected
Summary
Mitochondria are vital cellular organelles for energy production, as well as the regulation of diverse cellular processes, including heme and steroid synthesis, calcium homeostasis, redox. Mitochondrial ARSs (mtARSs) are all encoded by the nuclear genome, translated in cytoplasm, and imported into mitochondria. These mtARSs are key components of the mitochondrial translation apparatus and crucial for the expression of mitochondrial genes. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is the first disease recognized to have been associated with an mtARS gene. It is an autosomal recessive leukodystrophy caused by mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase [5]. Myoclonic epilepsy with ragged-red fibers (MERRF), a multi-systemic mitochondrial disease in which we previously demonstrated abnormalities of mitochondrial bioenergetics and morphology [15], was used as a positive control for mitochondrial dysfunction
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