Leber's hereditary optic neuropathy

Abstract

To clarify the bioenergetic relevance of mtDNA mutations in Leber's hereditary optic neuropathy (LHON), we investigated affected individuals and healthy carriers from six Italian LHON families harboring the 11778/ND4 and the 3460/ND1 mtDNA mutations. The enzymatic activities of mitochondrial complex I and its sensitivity to the potent inhibitors rotenone and rolliniastatin-2 were studied in mitochondrial particles from platelets, in correlation with mtDNA analysis of platelets and leukocytes. In platelets homoplasmic for mutant mtDNA, both 11778/ND4 and 3460/ND1 mutations induced resistance to rotenone and the 3460/ND1 mutation also provoked a marked decrease in the specific activity of complex I. Individuals heteroplasmic in platelets for either mutation showed normal biochemical features, indicating functional complementation of wild-type mtDNA. There was no correlation between the clinical status and mtDNA homo/heteroplasmy in platelets, but the biochemical features correlated with the mitochondrial genotype of platelets. In some cases, the degree of mtDNA heteroplasmy differed in platelets and leukocytes from the same individual with a prevalence of wild-type mtDNA in the platelets. These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues. The differential tissue heteroplasmy may be more relevant than previously thought in determining disease penetrance.

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

“…At low altitude the 3394C variant increases the risk of LHON (14)(15)(16)(17)(18), which is consistent with its 15-28% reduction in complex I-specific activity and a 7-17% reduction in maximum respiration rate.…”

“…The ND6 14459A mutation generates the most severe complex I defect (12) and causes LHON when heteroplasmic but dystonia when homoplasmic (11,13). The remaining mutations cause milder complex I defects (14)(15)(16)(17)(18) and cause LHON when near homoplasmic (8)(9)(10). For the milder LHON mutations (11778A, 3460A, 14484C) the penetrance of blindness is increased when the mutations arise on mtDNA haplogroup J (19)(20)(21)(22).…”

Leber's Hereditary Optic Neuropathy (LHON) Pathogenic Mutations Induce Mitochondrial-dependent Apoptotic Death in Transmitochondrial Cells Incubated with Galactose Medium

“…On the other hand, the complex I dysfunction in LHON seems mainly characterized by the common feature of affecting the interaction with the quinone substrate, and an increase of reactive oxygen species has been predicted as a direct consequence (9,10). Some recent studies are now supporting this hypothesis.…”

“…LHON is due to a massive acute or subacute retinal ganglion cell death, characteristically leading to central vision loss (2)(3)(4). These pathogenic mutations invariably affect complex I subunits, which possibly interact with the quinone substrate (9,10), and a combination of partial respiratory deficiency and increased oxidative stress is documented to be the pathological consequence in transmitochondrial cell systems (11)(12)(13)(14)(15). However, the mtDNA pathogenic mutations are a necessary, but not sufficient, condition to actually develop LHON, as suggested by the variable penetrance (2,16).…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…It is a matter of debate whether the presence of polymorphisms in the mtDNA or in nuclear genes encoding RC components could modify the effects of a particular mutation on the biosynthesis and electron transfer properties of the RC complexes. In this regard, a genetic modifying role for the mtDNA haplogroup background has often been proposed in the clinical expression of LHON, a maternally-inherited blinding disease that constitutes the most common mitochondrial disorder (Brown et al, 1997;Carelli et al, 1997;Hofmann et al, 1997;Torroni et al, 1997;Brown et al, 2002;Carelli et al, 2006;Yen et al, 2006;Hudson et al, 2007;Carelli et al, 2009). An increased complex I-dependent ROS production and decreased antioxidant defenses have been reportedly…”