OPA1 deficiency impairs oxidative metabolism in cycling cells, underlining a translational approach for degenerative diseases.

Dominant optic atrophy is an optic neuropathy with varying clinical symptoms and progression. A severe disorder is associated with certain OPA1 mutations and includes additional symptoms for >20% of patients. This underscores the consequences of OPA1 mutations in different cellular populations, not only retinal ganglionic cells. We assessed the effects of OPA1 loss of function on oxidative metabolism and antioxidant defences using an RNA-silencing strategy in a human epithelial cell line. We observed a decrease in the mitochondrial respiratory chain complexes, associated with a reduction in aconitase activity related to an increase in reactive oxygen species (ROS) production. In response, the NRF2 (also known as NFE2L2) transcription factor was translocated into the nucleus and upregulated SOD1 and GSTP1. This study highlights the effects of OPA1 deficiency on oxidative metabolism in replicative cells, as already shown in neurons. It underlines a translational process to use cycling cells to circumvent and describe oxidative metabolism. Moreover, it paves the way to predict the evolution of dominant optic atrophy using mathematical models that consider mitochondrial ROS production and their detoxifying pathways.

Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis.

OBJECTIVE: OPA1 mutations cause protein haploinsufficiency leading to dominant optic atrophy (DOA), an incurable retinopathy with variable severity. Up to 20% of patients also develop extraocular neurological complications. The mechanisms that cause this optic atrophy or its syndromic forms are still unknown. After identifying oxidative stress in a mouse model of the pathology, we sought to determine the consequences of OPA1 dysfunction on redox homeostasis. METHODS: Mitochondrial respiration, reactive oxygen species levels, antioxidant defenses, and cell death were characterized by biochemical and in situ approaches in both in vitro and in vivo models of OPA1 haploinsufficiency. RESULTS: A decrease in aconitase activity suggesting an increase in reactive oxygene species and an induction of antioxidant defenses was observed in cortices of a murine model as well as in OPA1 downregulated cortical neurons. This increase is associated with a decline in mitochondrial respiration in vitro. Upon exogenous oxidative stress, OPA1-depleted neurons did not further exhibit upregulated antioxidant defenses but were more sensitive to cell death. Finally, low levels of antioxidant enzymes were found in fibroblasts from patients supporting their role as modifier factors. INTERPRETATION: Our study suggests that the pro-oxidative state induced by OPA1 loss may contribute to DOA pathogenesis and that differences in antioxidant defenses can explain the variability in expressivity. Furthermore, antioxidants may be used as therapy as they could prevent or delay DOA symptoms in patients.