Abstract
Leber’s Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead to the development of LHON in synergy with the primary mtDNA mutation.
Highlights
Leber’s hereditary optic neuropathy (LHON) [OMIM 535 000] is one of the commonest mitochondrial inherited diseases [1]
Patients and Their Unaffected Relatives The samples employed in this study were cultured dermal fibroblasts, directly obtained from 7 affected Leber’s Hereditary Optic Neuropathy (LHON) patients from 3 unrelated pedigrees, 3 unaffected relatives from the 3 families, and 5 unrelated controls
LHON Patients and Their Unaffected Relatives Samples from individuals in three unrelated LHON pedigrees with different mitochondrial DNA (mtDNA) haplogroup backgrounds were employed in this study (Figure S1)
Summary
Leber’s hereditary optic neuropathy (LHON) [OMIM 535 000] is one of the commonest mitochondrial inherited diseases [1]. It is one of the common causes of blindness in young men, and more than 80% of LHON patients are male [2]. The three missense mitochondrial DNA (mtDNA) mutations 11778G.A, 14484T.C, and 3460G.A are the primary mutations responsible for 95% of LHON cases [4]. These mutations change amino acid R340H, M64V and A52T in ND4, ND6 and ND1 subunits of complex I of mitochondrial OXPHOS respectively. The coordinated expressions of imported nuclear encoded proteins with the 13 mtDNA-encoded proteins are crucial for the integrity of mitochondrial function
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