// Hesti Lina Wiraswati 1,2,3,4,5 , Emilie Hangen 1,2,3,4 , Ana Belén Sanz 1,2,3,4,6 , Ngoc-Vy Lam 1,2,3,4 , Camille Reinhardt 3,4,7 , Allan Sauvat 1,2,3,8 , Ariane Mogha 1,2,3,4 , Alberto Ortiz 6 , Guido Kroemer 1,2,3,8,9,10,11,12,* and Nazanine Modjtahedi 3,4,7,* 1 Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France 2 INSERM, U1138, Paris, France 3 Gustave Roussy Cancer Campus, Villejuif, France 4 Faculty of Medicine, Université Paris-Saclay, Kremlin-Bicêtre, France 5 Institut Teknologi Bandung (ITB), Bandung, Indonesia 6 Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz UAM and REDINREN, Madrid, Spain 7 INSERM, U1030, Villejuif, France 8 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France 9 Université Paris Descartes, Sorbonne Paris Cité, Paris, France 10 Université Pierre et Marie Curie, Paris, France 11 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France 12 Department of Women’s and Children’s Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden * These authors share senior co-authorship Correspondence to: Nazanine Modjtahedi, email: // Guido Kroemer, email: // Keywords : mitochondria, quinone metabolization, oxidative stress, protein arylation, Autophagy Received : March 13, 2016 Accepted : September 30, 2016 Published : October 11, 2016 Abstract Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.
Hypomorphic mutation of apoptosis-inducing factor (AIF) in the whole body or organ-specific knockout of AIF compromises the activity of respiratory chain complexes I and IV, as it confers resistance to obesity and diabetes induced by high-fat diet. The mitochondrial defect induced by AIF deficiency can be explained by reduced AIF-dependent mitochondrial import of CHCHD4, which in turn is required for optimal import and assembly of respiratory chain complexes. Here we show that, as compared to wild type control littermates, mice with a heterozygous knockout of CHCHD4 exhibit reduced weight gain when fed with a Western style high-fat diet. This finding suggests widespread metabolic epistasis among AIF and CHCHD4. Targeting either of these proteins or their functional interaction might constitute a novel strategy to combat obesity.
Abstract Development, physiological functions, and pathologies of the brain depend on tight interactions between neurons and different types of glial cells, such as astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. Assessing the relative contribution of different glial cell types is required for the full understanding of brain function and dysfunction. Over the recent years, several technological breakthroughs were achieved, allowing “glio‐scientists” to address new challenging biological questions. These technical developments make it possible to study the roles of specific cell types with medium or high‐content workflows and perform fine analysis of their mutual interactions in a preserved environment. This review illustrates the potency of several cutting‐edge experimental approaches (advanced cell cultures, induced pluripotent stem cell (iPSC)‐derived human glial cells, viral vectors, in situ glia imaging, opto‐ and chemogenetic approaches, and high‐content molecular analysis) to unravel the role of glial cells in specific brain functions or diseases. It also illustrates the translation of some techniques to the clinics, to monitor glial cells in patients, through specific brain imaging methods. The advantages, pitfalls, and future developments are discussed for each technique, and selected examples are provided to illustrate how specific “gliobiological” questions can now be tackled.
Since its discovery nearly a decade ago, apoptosis‐inducing factor (AIF) has had anything but a staid and uneventful existence. AIF was originally described as a mitochondrial intermembrane protein that, after apoptosis induction, can translocate to the nucleus and trigger chromatin condensation and DNA fragmentation. Over the years, an AIF‐mediated caspase‐independent cell death pathway has been defined. Rather than functioning as a general component of the cell death machinery, AIF is required for specific cell death pathways, including lethal responses to excitotoxins such as N ‐methyl‐ d ‐aspartate and glutamate, the DNA‐alkylating agent N ‐methyl‐ N '‐nitro‐ N ‐nitroso‐guanidine, hypoxia–ischemia, or growth factor deprivation. Also, important roles of AIF in mitochondrial metabolism and redox control, and more recently in obesity and diabetes, have been discovered. Much of our knowledge has come from studies of AIF orthologs in model organisms, Saccharomyces cerevisiae , Caenorhabditis elegans , Drosophila melanogaster , and mice, which have also highlighted the importance of AIF in animal physiology and human pathology. Here, we discuss the manifold nature of AIF in cell life and death, with particular emphasis of its roles in vivo .
In many models of programmed cell death, the mitochondrial protein AIF translocates to the nucleus, where it induces the chromatin condensation and DNA degradation. However, today it is well established that this flavoprotein is bifunctional. In addition to its lethal function in the nucleus of dying cells, AIF plays a vital bioenergetic role in healthy ones by regulating mainly the activity of the mitochondrial respiratory chain complex I. Hypomorphic or deletion mutants of AIF have led to the generation of the first reliable mouse model of complex I deficiency syndrome, which leads to progressive ataxia and blindness due to neuronal degeneration, as well as a dilated cardiomyopathy, skeletal muscle atrophy and metabolic dysfunction. Here, we discuss recent progress in the quest to understand AIF’s involvement in cell survival and in the regulation of mitochondrial respiratory chain complex I.
