Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy: a model of mitochondrial neurodegeneration

Abstract

Leber's hereditary optic neuropathy (LHON) was the first maternally inherited disease to be associated with point mutations in mitochondrial DNA and is now considered the most prevalent mitochondrial disorder. The pathology is characterized by selective loss of ganglion cells in the retina leading to central vision loss and optic atrophy, prevalently in young males. The pathogenic mtDNA point mutations for LHON affect complex I with the double effect of lowering the ATP synthesis driven by complex I substrates and increasing oxidative stress chronically. In this review, we first consider the biochemical changes associated with the proton-translocating NADH-quinone oxidoreductase of mitochondria in cybrid cells carrying the most common LHON mutations. However, the LHON cybrid bioenergetic dysfunction is essentially compensated under normal conditions, i.e. in glucose medium, but is unrevealed by stressful conditions such as growing cybrids in glucose free/galactose medium, which forces cells to rely only on respiratory chain for ATP synthesis. In fact, the second part of this review deals with the investigation of LHON cybrid death pathway in galactose medium. The parallel marked changes in antioxidant enzymes, during the time-course of galactose experiments, also reveal a relevant role played by oxidative stress. The LHON cybrid model sheds light on the complex interplay amongst the different levels of biochemical consequences deriving from complex I mutations in determining neurodegeneration in LHON, and suggests an unsuspected role of bioenergetics in shaping cell death pathways.

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

“…In addition to optic atrophy, some patients affected with LHON may have other neurological symptoms related to lesions of the white matter of the central nervous system (Nikoskelainen et al, 1995). More than 95% of the patients carry one of the three primary LHON-causing mtDNA mutations at nucleotide positions 11778, 3460 and 14484 in genes encoding subunits of the respiratory chain complex I. Incidentally, these mutations have been shown to seriously impair ATP synthesis, which depends on complex I activity, in transmitochondrial cybrid models (Carelli et al, 2004).…”

Effects of OPA1 mutations on mitochondrial morphology and apoptosis: Relevance to ADOA pathogenesis

“…This disease is characterized by the insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, abnormalities of color vision and caecocentral visual field scotoma (3)(4)(5). Electrophysiological and histopathological studies have suggested that the underlying defect is retinal ganglion cell (RGC) degeneration leading to atrophy of the optic nerve (3,6), as observed in Leber hereditary optic atrophy (LHON) a maternally transmitted disease caused by mtDNA mutations (7).…”

Leber's Hereditary Optic Neuropathy–Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India

“…1,2 Clinical features include the slowly progressive loss of central vision with apoptotic death of retinal ganglion cells and optic nerve degeneration. 3,4 Age of onset varies from adolescence to young adults, with late-onset disease also reported.…”