Vahsen, N. et al. AIF deficiency compromises oxidative phosphorylation. EMBO J. 23, 4679-4689

CNRS-UMR8125, Institut Gustave Roussy, Villejuif, France.
The EMBO Journal (Impact Factor: 10.43). 12/2004; 23(23):4679-89. DOI: 10.1038/sj.emboj.7600461
Source: PubMed


Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death.

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Available from: Mauro Piacentini, Dec 09, 2014
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    • "In addition , several complex I assembly factors have been shown to be dual-function proteins. For example, ACAD9 is also involved in fatty acid β-oxidation (Haack et al. 2010) and AIF is a mitochondrial flavoprotein playing a role during apoptosis (Vahsen et al. 2004). "
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    ABSTRACT: L-Galactono-1,4-lactone dehydrogenase (GLDH) catalyses the last enzymatic step of the ascorbate biosynthetic pathway in plants. GLDH is localised to mitochondria and several reports have shown that GLDH is associated with complex I of the respiratory chain. In a gldh knock-out mutant, complex I is not detectable, suggesting that GLDH is essential for complex I assembly or stability. GLDH has not been identified as a genuine complex I subunit, instead, it is present in a smaller, lowly abundant version of complex I called complex I*. In addition, GLDH activity has also been detected in smaller protein complexes within mitochondria membranes. Here, we investigated the role of GLDH during complex I assembly. We identified GLDH in complexes co-localising with some complex I assembly intermediates. Using a mutant that accumulates complex I assembly intermediates, we confirmed that GLDH is associated with the complex I assembly intermediates of 400 and 450 kDa. In addition, we detected accumulation of the 200 kDa complex I assembly intermediate in the gldh mutant. Taken together, our data suggest that GLDH is an assembly factor of the membrane arm of complex I. This function appears to be independent of the role of GLDH in ascorbate synthesis, as evidenced by the ascorbate-deficient mutant vtc2-1 accumulating wild-type levels of complex I. Therefore, we propose that GLDH is a dual-function protein that has a second, non-enzymatic function in complex I assembly as a plant-specific assembly factor. We propose an updated model for complex I assembly that includes complex I* as an assembly intermediate.
    Plant Molecular Biology 11/2015; DOI:10.1007/s11103-015-0400-4 · 4.26 Impact Factor
    • "Additionally, GLUT4-silenced cells displayed reduced levels of lactate (Fig. 3B) which is in agreement with a restructuring of the metabolic flux from fermentation to oxidative phosphorylation (OXPHOS). Further confirmation of this phenomenon was obtained through analysis of cytochrome oxidase subunit I (CO-1) levels, an indicator of OXPHOS (Vahsen et al., 2004), as CO-1 levels were higher in GLUT4-silenced cells than those detected in the corresponding MCF7 control cells (Fig. 3C). Altogether, these results support that MCF7 cells undergone metabolic reprogramming as a consequence of the reduction in glucose uptake. "
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    ABSTRACT: Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2015; 230(1). DOI:10.1002/jcp.24698 · 3.84 Impact Factor
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    • "The mitochondrial flavoprotein AIF is synthesised in the cytoplasm as a ~ 67 kDa precursor. Its maturation involves a proteolytical cleavage of the precursor to a ubiquitously expressed ~ 62 kDa form [20]. Mature AIF is imbedded into the inner mitochondrial membrane where it is involved in organizing and/or maintaining the structural integrity of the respiratory chain complex-I [23,24]. Indeed, deficiency in AIF expression is associated with reduced complex-I activity and decreased ATP production [24]. "
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    ABSTRACT: Background Recent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. However, the brain region specificity of caspase-independent PCD in AD-associated neurodegeneration is unknown. We therefore used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging. Results Increased expression of truncated AIF (tAIF), which is directly responsible for cell death induction, was observed at both 4- and 6-months of age in the cortex. Concomitant with the up-regulation of tAIF was an increase in the nuclear translocation of this protein. Heightened tAIF expression or translocation was not observed in the hippocampus or cerebellum, which were used as AD-vulnerable and relatively AD-spared regions, respectively. The cortical alterations in tAIF levels were accompanied by increased Bax expression and mitochondrial translocation. This effect was preceded by a significant reduction in ATP content and an increase in reactive oxygen species (ROS) production, detectable at 2 months of age despite negligible amounts of amyloid-beta peptides (Aβ). Conclusions Taken together, these data suggest that AIF is likely to play a region-specific role in AD-related caspase-independent PCD, which is consistent with aging-associated mitochondrial impairment and oxidative stress.
    BMC Neuroscience 06/2014; 15(1):73. DOI:10.1186/1471-2202-15-73 · 2.67 Impact Factor
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