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AIF-regulated oxidative phosphorylation supports lung cancer development

Abstract : Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras G12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of Kras G12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout Kras G12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.
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https://hal.archives-ouvertes.fr/hal-02355955
Contributor : Nazanine Modjtahedi <>
Submitted on : Tuesday, January 5, 2021 - 12:33:43 PM
Last modification on : Tuesday, January 5, 2021 - 2:19:34 PM

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s41422-019-0181-4.pdf
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Shuan Rao, Laura Mondragón, Blanka Pranjic, Toshikatsu Hanada, Gautier Stoll, et al.. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell Research, Nature Publishing Group, 2019, 29 (7), pp.579-591. ⟨10.1038/s41422-019-0181-4⟩. ⟨hal-02355955⟩

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