Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G

Leber's hereditary optic neuropathy (LHON) is associated with mitochondrial DNA point mutations affecting different subunits of complex I. By replacing glucose with galactose in the medium, cybrids harboring each of the three LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ND6) suffered a...

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Bibliographic Details
Published in:Apoptosis (London) 2005-10, Vol.10 (5), p.997-1007
Main Authors: Zanna, C, Ghelli, A, Porcelli, A M, Martinuzzi, A, Carelli, V, Rugolo, M
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Amino Acid Chloromethyl Ketones - pharmacology
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Apoptosis Inducing Factor - physiology
Cells, Cultured
Culture Media
Electron Transport Complex I - genetics
Endodeoxyribonucleases - physiology
Galactose - metabolism
Galactose - pharmacology
Humans
Hybrid Cells
Mitochondrial DNA
Optic Atrophy, Hereditary, Leber - genetics
Optic Atrophy, Hereditary, Leber - physiopathology
Retinal Ganglion Cells - cytology
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Summary:Leber's hereditary optic neuropathy (LHON) is associated with mitochondrial DNA point mutations affecting different subunits of complex I. By replacing glucose with galactose in the medium, cybrids harboring each of the three LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ND6) suffered a profound ATP depletion over a few hours and underwent apoptotic cell death, which was caspase-independent. Control cybrids were unaffected. In addition to cytochrome c, apoptosis inducing factor (AIF) and endonuclease G (EndoG) were also released from the mitochondria into the cytosol in LHON cybrids, but not in control cells. Exposure of isolated nuclei to cytosolic fractions from LHON cybrids maintained in galactose medium caused nuclear fragmentation, which was strongly reduced by immuno-depletion with anti-AIF and anti-EndoG antibodies. In conclusion, the caspase-independent death of LHON cybrids incubated in galactose medium is triggered by rapid ATP depletion and mediated by AIF and EndoG.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-005-0742-5