title: Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation.
abstract: Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON expression, complex I- and complex II-dependent adenosine triphosphate synthesis rates (CI-ATP, CII-ATP) were determined in digitonin-permeabilized peripheral blood mononuclear cells (PBMCs) of thirteen healthy controls and for each primary mutation of a minimum of three unrelated patients and of three unrelated carriers with normal vision and were normalized per mitochondrion (citrate synthase activity) or per cell (protein content). We found that in mitochondria, CI-ATP and CII-ATP were impaired irrespective of the primary LHON mutation and clinical expression. An increase in mitochondrial density per cell compensated for the dysfunctional mitochondria in LHON carriers but was insufficient to result in a normal biochemical phenotype in early-onset LHON patients.
authors.affiliation: Department of Neurology, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Korsten
authors.forename: Irenaeus F M
authors.initials: IF
authors.lastname: de Coo
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: L Elly A
authors.initials: LE
authors.lastname: de Wit
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Wim
authors.initials: W
authors.lastname: Sluiter
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011522:Protons; D055815:Young Adult
chemical_list: D011522:Protons; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I