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Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium

Ghelli, A; Zanna, C; Porcelli, AM; Schapira, AH; Martinuzzi, A; Carelli, V; Rugolo, M; (2003) Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium. Journal of Biological Chemistry , 278 (6) pp. 4146-4150. Gold open access

Abstract

Lebers hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is associated with mitochondrial DNA pathogenic point mutations affecting different subunits of complex I. We here report that osteosarcoma-derived cybrid cell lines harboring one of the three most frequent LHON pathogenic mutations, at positions 11778/ND4, 3460/ND1 and 14484/ND6, undergo cell death when galactose replaces glucose in the medium, contrary to control cybrids that maintain some growth capabilities. This is a well-known way to produce a metabolic stress forcing the cells to rely on mitochondrial respiratory chain to produce ATP. We demonstrate that LHON cybrid cells death is apoptotic showing chromatin condensation and nuclear DNA laddering. Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells compared to controls. Cybrids bearing the 3460/ND1 and 14484/ND6 mutations seemed more readily prone to undergo apoptosis compared to the 11778/ND4 mutation. In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria

Type: Article
Title: Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium
Open access status: An open access publication
Additional information: UI - 0 DA - 20021125 IS - 1083-351X LA - ENG PT - JOURNAL ARTICLE
Keywords: ACTIVATION, apoptosis, As, ATP, CASCADE, cell, Cell Death, Cell Line, Cell lines, CELL-DEATH, CELL-LINE, CELL-LINES, CELLS, CHAIN, Chromatin, COMPLEX, complex I, COMPLEXES, control, Cytochrome c, Cytosol, DEATH, DNA, Form, Galactose, Glucose, growth, hereditary, HEREDITARY OPTIC NEUROPATHY, INDUCE, INVOLVEMENT, LA, LINE, LINES, loss, MECHANISM, media, metabolic, metabolism, Mitochondria, mitochondrial, mitochondrial DNA, Mutation, MUTATIONS, neuropathy, nuclear, optic neuropathy, oxidative, oxidative metabolism, OXIDATIVE-METABOLISM, Point Mutation, POINT MUTATIONS, POSITION, release, report, RESPIRATORY, RESPIRATORY CHAIN, stress, SUBUNIT, SUBUNITS, vision
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/127659
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