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.

Download full-text


Available from: Mauro Piacentini, Dec 09, 2014
19 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
    • "p53 activates the expression of the synthesis of cytochrome c oxidase 2 (SCO2), which facilitates the assembly of complex IV (cytochrome c oxidase).[49] It also transcriptionally enhances apoptosis-inducing factor (AIF),[50] a mitochondrial pro-apoptotic protein that is also required for the function of complex I (NADH dehydrogenase).[51] Thus, p53 helps shift the production of ATP from glycolysis to oxidative phosphorylation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumor suppressor p53 plays a pre-eminent role in protecting against cancer, through its ability to sense various stresses and in turn invoke anti-proliferative and repair responses. Emerging evidence suggest that p53 is both a central sentinel for metabolic stresses and a master regulator of metabolic fluxes. This newly identified function of p53, along with the ability of p53 to induce senescence, appears to be crucial for the prevention of oncogenic transformation. A better understanding of the reciprocal regulation of p53 and metabolism, as well as p53-mediated connection between metabolism and senescence, may lead to the identification of valuable targets for tumor therapy.
    Journal of Carcinogenesis 11/2013; 12:21. DOI:10.4103/1477-3163.122760
    • "Aif-null embryonic stem cells and HeLa cells show a quantitative reduction in complex I subunits along with reduction of complex I activity and a partial reduction in complex III activity. It is thus presumed that Aif is important for the structural and functional organization of complex I and probably of complex III45. In addition to the oxidoreductase function of Aif, it has a clear functional domain for DNA binding activity46. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.
    The Indian Journal of Medical Research 11/2013; 138(5):577-90. · 1.40 Impact Factor
Show more