Original Article | Published:

GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization

Oncogene volume 26, pages 26062620 (19 April 2007) | Download Citation

Abstract

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.

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Acknowledgements

We thank C Henry (platform PAPSS, INRA, http://www.jouy.inra.fr/unites/proteines/papss/) and C Longin (platform MIMA2, http://voxel.jouy.inra.fr/mima2) for their professional assistance in mass spectrometry and electron microsocopy, respectively. This work was supported by grants funded by ARC, CNRS and French Ministry of Research. (to CB), by a special grant of the League against Cancer and by the European Union (Trans-Death, RIGHT) (to GK). MLB received a postdoctoral fellowship of CNRS. AT and AD received a doctoral and post doctoral fellowships from the Ligue Contre le Cancer.

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Affiliations

  1. CNRS UMR 8159, Université de Versailles/SQY, Versailles, France

    • A Tarze
    • , A Deniaud
    • , M Le Bras
    • , E Maillier
    •  & C Brenner
  2. INRA UMR STLO, Rennes, France

    • D Molle
    •  & G Jan
  3. IGR, CNRS UMR 8125, Villejuif, France

    • N Larochette
    • , N Zamzami
    •  & G Kroemer

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Correspondence to C Brenner.

Glossary

AIF

apoptosis-inducing factor

ANT

adenine nucleotide translocator

Cyt c

cytochrome c

CsA

cyclosporin A

DIDS

4,4′-diisothiocyanatostilbene-2,2′-disulfonate

DTT

dithiotheritol

m

mitochondrial transmembrane potential

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

mClCCP

carbonylcyanide m-chlorophenylhydrazone

MMP

mitochondrial membrane permeabilization

MUP

4-methylumbelliferyl phosphate

nanoLC MS/MS

nano liquid chromatography mass spectroscopy/mass spectroscopy

IM

inner membrane

OM

outer membrane

PI

propidium iodide

ROS

reactive oxygen species

PTPC

permeability transition pore complex

PBR

peripheral benzodiazepine receptor

VDAC

voltage-dependent anion channel

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DOI

https://doi.org/10.1038/sj.onc.1210074

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