Molecular characterization of mitochondrial apoptosis-inducing factor

Susin, Santos A.; Lorenzo, Hans K.; Zamzami, Naoufal; Marzo, Isabel; Snow, Bryan E.; Brothers, Greg M.; Mangion, Joan; Jacotot, Etienne; Costantini, Paola; Loeffler, Markus; Larochette, Nathanael; Goodlett, David R.; Aebersold, Ruedi; Siderovski, David P.; Penninger, Josef M.; Kroemer, Guido

doi:10.1038/17135

Cited by 4,060Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Molecular characterization of mitochondrial apoptosis-inducing factor

Susin, Santos A., Lorenzo, Hans K., Zamzami, Naoufal, Marzo, Isabel, Snow, Bryan E., Brothers, Greg M., Mangion, Joan, Jacotot, Etienne +8 more·1999·Nature

DOI 10.1038/17135

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Abstract

Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.

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AIF migration from mitochondria to nucleus mediates apoptosis in a manner that cannot be blocked by overexpression of antiapoptotic Bcl-2 or by caspase inhibition.
“Consistent with previous reports (407), AIF migration from the mitochondria to nucleus was found to mediate apoptosis in a manner that could not be blocked by overexpression of the antiapoptotic Bcl-2 or by caspase inhibition.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [407]

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Authors: Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., & Kroemer, G.
Affiliations: Institut Pasteur (FR)
Centre National de la Recherche Scientifique (FR)
University of Toronto (CA)
University of Washington (US)
Corresponding author: Kroemer, Guido
ORCID: Lorenzo, Hans K.
Marzo, Isabel
Jacotot, Etienne
Costantini, Paola
Loeffler, Markus
Goodlett, David R.
Aebersold, Ruedi
Siderovski, David P.
Penninger, Josef M.
Kroemer, Guido
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1999-02
Volume: 397
Issue: 6718
Pages: 441-446
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/17135
OpenAlex: W2159650080
Cited by: 4,060
References: 30
Citations by year: 2026: 30 · 2025: 43 · 2024: 58 · 2023: 65 · 2022: 68 · 2021: 110 · 2020: 84 · 2019: 91 · 2018: 109 · 2017: 99 · 2016: 100 · 2015: 133 · 2014: 102 · 2013: 154 · 2012: 167
FWCI: 87.85
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Padua Research Archive (University of Padova) (submittedVersion)
Funders: Amgen
Institut National de la Santé et de la Recherche Médicale
Centre National de la Recherche Scientifique
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: apoptosis-inducing factor, mitochondrial apoptosis, flavoprotein, cytochrome c release, caspase-9, chromatin condensation, DNA fragmentation, mitochondrial membrane potential, phosphatidylserine exposure, Bcl-2, mitochondrial permeability transition, nuclear translocation
MeSH terms: Amino Acid Sequence, Animals, Antibodies, Cell Line, Cell Nucleus, Cell-Free System, Chromatin, Cytochrome c Group, Flavoproteins, HeLa Cells, Humans, Intracellular Membranes, Membrane Proteins, Microinjections, Mitochondria, Molecular Sequence Data, Recombinant Proteins, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Apoptosis Inducing Factor, Mice, Rats

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Molecular characterization of mitochondrial apoptosis-inducing factor

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