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OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144914 | GEO | 2020/02/08

REPOSITORIES: GEO

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2023-05-08 | GSE224780 | GEO

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Project description:Leber’s hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by homoplasmic mutations in complex I subunit genes, and is characterized by incomplete penetrance. The mechanism of low penetrance of complex I mutation is still largely unclear today. In this study, we created the patient-specific induced pluripotent stem cells (iPSCs) from MT-ND4 mutated LHON affected patient, asymptomatic mutation carrier and control, and differentiated them into retinal ganglion cells (RGCs) for pathogenesis survey. We observed the following phenotypic features in the LHON-specific RGCs as compared to the control: 1) enhanced mitochondrial biogenesis in affected and carriers; 2) compensatory increased mitochondrial complex I activity in carrier, but not in affected patient; 3) reduced spare respiratory activity in affected and carrier. Microarray profiling of LHON-specific RGCs revealed abundant overexpression of genes encoding components of cell cycle regulation machinery as compared to the control.

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OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

Project description:OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy

| PRJNA605325 | ENA

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