OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy
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ABSTRACT:
PROVIDER: PRJNA605325 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11040359.fastq.gz | Fastqsanger.gz | |||
| SRR11040360.fastq.gz | Fastqsanger.gz | |||
| SRR11040361.fastq.gz | Fastqsanger.gz | |||
| SRR11040362.fastq.gz | Fastqsanger.gz | |||
| SRR11040363.fastq.gz | Fastqsanger.gz |
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Project description:Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables asymptomatic carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G>A lymphoblasts and primary fibroblasts from both carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in carrier and affected cells, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells, our results indicate that affected cells suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.
2020-02-08 | GSE144914 | GEO
Project description:Leber hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. These mtDNA pathogenic mutations have variable clinical penetrance. Recent linkage evidence raised the possibility that the nuclear gene optic atrophy 1 (OPA1) determines whether mtDNA mutation carriers develop blindness. To validate these findings we studied OPA1 in three independent LHON cohorts: sequencing the gene in discordant male sib pairs, carrying out a family-based association study of common functional genetic variants, and carrying out a population-based association study of the same genetic variants.We tested 3 hypothesis in three separate study groups. Study group 1: Direct sequencing of OPA1 coding regions was performed using sequencing methodologies (Applied Biosystems, Foster City, CA). Chromatograms were compared with the GenBank reference sequence NM_015560.1. Splice-site prediction was performed using GeneSplicer. Study group 2: Genotyping for rs166850 and rs10451941 was performed by restriction fragment length polymorphism (RFLP) analysis with specific primers for both genotypes, using The restriction enzymes RsaI and FspBI to discriminate genotypes. Study group 3: Genotyping for rs166850 and rs10451941 was performed by primer extension of allele-specific extensions products by matrix-associated laser desorption/ionisation time-of-flight (MALDI-TOF, Seqeunom, San Diego, CA) mass spectrometry. Allele and genotype frequencies were compared using Pearson's chi-square test. Multiple logistic regression was performed to look for interactions between the variables. All analyses were performed using SPSS software version 17.0 (SPSS Inc.).In all three groups we were unable to find an association between OPA1 genetic variation and visual failure in LHON mtDNA mutation carriers.Our findings suggest that genetic variation in OPA1 is unlikely to make a major contribution to the risk of blindness in LHON mutation carriers.
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