LHON: Mitochondrial Mutations and More

Abstract

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the ‘primary LHON mutations’ to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.

The Ageing Brain, Mitochondria and Neurodegeneration

“…More recently, the phenotypic spectrum has broadened to include neurodegenerative disease [ 72 ], typically as a function of a primary mtDNA defect. Leber's hereditary optic neuropathy (LHON) is the commonest cause of maternally inherited blindness and a cardinal example of how mtDNA mutations cause neurodegeneration [ 73 ]. MtDNA mutations (m.3460G>A, m.11778G>A and m.14484T>C in ~90 % of cases) in NADH-dehydrogenase subunits (complex I) reduce cellular energy and increase oxidative stress and ROS production to cause a selective loss of retinal ganglion cells (RGC) in the retina whilst sparing the retinal pigmented epithelium and photoreceptor layer [ 74 ].…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Although approximately 45 mutations have been linked to LHON, all of the mutations identified in symptomatic individuals are secondary to amino-acid substitutions in the mitochondrial DNA coding for the respiratory chain subunits of the nicotinamide adenine dinucleotide ubiquinone oxidoreductase (complex I). Of the six mutations localized within this complex, the mutation in polypeptides ND1 (G3460A), ND4 (G11778A), and ND6 (T14484C) account for approximately 95% of all cases (Kirches 2011); mutation G11778 in ND4 appears to be the most common, accounting for 50-70% of all LHON. These latter mutations cause a defect in complex I function, resulting in the loss of energetic efficiency, increased oxidative stress, and an increase in the risk for apoptotic cell death.…”

A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia

“…Whereas in the case of NDUFAF7, as a mitochondrial assembly factor, it is involved in mitochondrial respiratory chain system, 31 and previous research showed that the decline in ATP synthesis via mitochondrial energy metabolism leads to severe visual impairment. 32 Thus, we decided to focus on the function investigation of the mutant (MT) NDUFAF7 detected as a de novo missense mutation (p.D266E) in this family. As for RHO c.310G>A, it was found in RP patients, and no clear evidence of its pathogenicity has been reported.…”