The Harlequin mutant mouse, characterized by loss of function of
apoptosis-inducing factor, represents a reliable genetic model that resembles pathologies caused by human
mitochondrial complex I deficiency. Therefore, we extensively characterized the
retinal morphology and function of Harlequin mice during the course of neuronal cell death leading to
blindness, with the aim of preventing
optic atrophy. Retinas and optic nerves from these mice showed an isolated respiratory chain complex I defect correlated with retinal ganglion cell loss,
optic atrophy, glial and microglial cell activation. All of these changes led to irreversible vision loss. In control mice, retinas AIF1
messenger RNA was 2.3-fold more abundant than AIF2, both messenger RNAs being sorted to the mitochondrial surface. In Harlequin mouse retinas, there was a 96% decrease of both AIF1 and AIF2
messenger RNA steady-state levels. We attained substantial and long-lasting protection of retinal ganglion cell and optic nerve integrity, the preservation of complex I function in optic nerves, as well as the prevention of glial and microglial responses after intravitreal administration of an AAV2 vector containing the full-length open reading frame and the
3' untranslated region of the AIF1 gene. Therefore, we demonstrate that gene therapy for
mitochondrial diseases due to mutations in nuclear
DNA can be achieved, so long as the 'therapeutic gene' permits the accurate cellular localization of the corresponding
messenger RNA.