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June 7, 2023 • ✎ STRIA TECH

Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4−/− Mouse Model of Mitochondrial Complex I Deficiency

Topics:

Ocular and CNS Toxicity Models

Rare and Inherited CNS and Eye Disorders

Rare Disease

Retinal Degeneration

Publication

Translational Vision Science & Technology (Aug 01, 2022) Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4^−/− Mouse Model of Mitochondrial Complex I Deficiency

Avrutsky MI, Lawson JM, Smart JE, Chen CW, Troy CM

DOI: 10.1167/tvst.11.8.5 >>

Mitochondrial complex I disorders are a heterogeneous group of rare inherited diseases caused by mutations affecting proteins in the mitochondrial electron transport chain. Neurological and ophthalmic pathologies are common to many forms of complex I deficiency, due to the high energy demands of central nervous system tissues. Avrutsky et al characterized one such mouse model, carrying a mutation in Ndufs4 (NADH:ubiquinone oxidoreductase Fe-S protein 4), which shows fast retinal degeneration within only a few weeks. They show that a range of non-invasive techniques (OCT for structural changes, ERG for electrophysiological properties, and OMR with our OptoDrum for behavioral assessment) can capture relevant measures of disease progression.

Purpose: To characterize postnatal ocular pathology in a Ndufs4^−/− mouse model of complex I deficiency using noninvasive retinal imaging and visual testing. Methods: Ndufs4^−/− mice and wild-type (WT) littermates were analyzed at 3, 5, and 7 weeks postnatal. Retinal morphology was visualized by optical coherence tomography (OCT). OCT images were analyzed for changes in retinal thickness and reflectivity profiles. Visual function was assessed by electroretinogram (ERG) and optomotor reflex (OMR). Results: Ndufs4^−/− animals have normal OCT morphology at weaning and develop inner plexiform layer atrophy over weeks 5 to 7. Outer retinal layers show hyporeflectivity of the external limiting membrane (ELM) and photoreceptor ellipsoid zone (EZ). Retinal function is impaired at 3 weeks, with profound deficits in b-wave, a-wave, and oscillatory potential amplitudes. The b-wave and oscillatory potential implicit times are delayed, but the a-wave implicit time is unaffected. Ndufs4^−/− animals have normal OMR at 3 weeks and present with increasing acuity and contrast OMR deficits at 5 and 7 weeks. Physiological thinning of inner retinal layers, attenuation of ELM reflectivity, and attenuation of ERG b- and a-wave amplitudes occur in WT C57BL/6 littermates between weeks 3 and 7. Conclusions: Noninvasive ocular imaging captures early-onset retinal degeneration in Ndufs4^−/− mice and is a tractable approach for investigating retinal pathology subsequent to complex I deficiency. Translational relevance: Ophthalmic imaging captures clinically relevant measures of retinal disease in a fast-progressing mouse model of complex I deficiency consistent with human Leigh syndrome.