GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a pleiotropic enzyme that is overexpressed in apoptosis and in several human chronic pathologies. Here, we report that the protein accumulates in mitochondria during apoptosis, and induces the pro-apoptotic mitochondrial membrane permeabilization, a decisive event of the intrinsic pathway of apoptosis. GAPDH was localized by immunogold labeling and identified by matrix-assisted laser desorption/ionization-time of flight and nano liquid chromatography mass spectroscopy/mass spectroscopy in the mitochondrion of various tissues and origins. In isolated mitochondria, GAPDH can be imported and interact with the voltage-dependent anion channel (VDAC1), but not the adenine nucleotide translocase (ANT). The protein mediates a cyclosporin A-inhibitable permeability transition, characterized by a loss of the inner transmembrane potential, matrix swelling, permeabilization of the inner mitochondrial membrane and the release of two pro-apoptotic proteins, cytochrome c and apoptosis-inducing factor (AIF). This novel function of GAPDH might have implications for the understanding of mitochondrial biology, oncogenesis and apoptosis.
Tarze
A
A
CNRS UMR 8159, Université de Versailles/SQY, Versailles, France.
Deniaud
A
A
Le Bras
M
M
Maillier
E
E
Molle
D
D
Larochette
N
N
Zamzami
N
N
Jan
G
G
Kroemer
G
G
Brenner
C
C
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
D007166:Immunosuppressive Agents; C494764:Vdac1 protein, rat; D016572:Cyclosporine; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D050995:Voltage-Dependent Anion Channel 1; D053148:Caspase 3