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Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

ABSTRACT: Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is a prominent ocular manifestation of mitochondrial dysfunction. Although transgenic mice lacking the mitochondrial complex I accessory subunit NDUFS4 develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death and makes this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathies. Theoretically, RGC-specific inactivation of ndufs4 would allow characterization of RGC degeneration over a longer time course, provided that RGC death from mitochondrial dysfunction is a cell-autonomous process. We demonstrate that the vesicular glutamate transporter VGLUT2 may be exploited to drive robust Cre recombinase expression in RGCs without any expression observed in directly neighboring retinal cell types. Deletion of ndufs4 in RGCs resulted in reduced expression of NDUFS4 protein within the optic nerves of Vglut2-Cre;ndufs4loxP/loxP mice. RGC degeneration in Vglut2-Cre;ndufs4loxP/loxP retinas commenced around postnatal day 45 (P45) and progressed to loss of two-thirds of RGCs by P90, confirming that intrinsic complex I dysfunction is sufficient to induce RGC death. The rapidly-developing optic atrophy makes the Vglut2-Cre;ndufs4loxP/loxP mouse line a promising preclinical model for testing therapies for currently untreatable mitochondrial optic neuropathies such as Leber Hereditary Optic Neuropathy.

SUBMITTER: Wang L

PROVIDER: S-EPMC7529752 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterized by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. More than 60% of genetically confirmed patients with DOA carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null induced pluripotent stem cell (iPSC) (OPA1+/-) through clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G>A, DOA plus [DOA]+ iPSC) and CRISPR/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+/-, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+/- and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions.

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Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

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