Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus

Delavallée, Laure; Mathiah, Navrita; Cabon, Lauriane; Mazeraud, Aurélien; Brunelle-Navas, Marie-Noëlle; Lerner, Letícia Koch; Tannoury, Mariana; Prola, Alexandre; Moreno‐Loshuertos, Raquel; Baritaud, Mathieu; Vela, Laura; Garbin, Kevin; Garnier, Delphine; Lemaire, Christophe; Langa‐Vives, Francina; Cohen-Salmon, Martine; Fernández‐Silva, Patricio; Chrétien, Fabrice; Migeotte, Isabelle; Susin, Santos A.

doi:10.1016/j.molmet.2020.101027

Cited by 27 publications

(25 citation statements)

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“…Moreover, the binding of the second coenzyme molecule, NAD(H) B , is proposed to allosterically regulate the monomer‐dimer transition, additionally attributing to AIF a function as a sensor of the mitochondrial redox status 9,15–17 . Altogether, AIF plays key roles in controlling the mitochondrial OXPHOS/metabolism, as shown by a recent study that using a novel AIF‐deficient mouse model confirms that its deficiency destabilises mitochondrial ETC and induces supercomplex disorganization, mitochondrial transmembrane potential loss and high generation of mitochondrial reactive oxygen species (ROS) 55 . This model shows AIF as a key factor regulating cell differentiation and fate.…”

Section: The Mitochondrial Pro‐life Roles Of the Aif Familymentioning

confidence: 97%

“…Clarifying the molecular and functional implications of these mutations is a challenge that will be critical to provide proper genetic counselling in patients suffering from these disorders. Recent observations linking mitochondrial signals and metabolism regulated by AIF to cell development and fate also point to the mitochondrial AIF‐mediated OXPHOS/metabolism as an emerging target in the development of new therapeutic approaches for diseases related to mitochondrial OXPHOS alteration/dysfunction 55 …”

Section: The Aif Family In Health and Diseasementioning

confidence: 99%

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The apoptosis‐inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei

2020

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In Homo sapiens, the apoptosis‐inducing factor (AIF) family is represented by three different proteins, known as AIF, AMID and AIFL, that have in common the mitochondrial localisation in healthy cells, the presence of FAD‐ and NADH‐dependent domains involved in an ‐albeit yet not well understood‐ oxidoreductase function and their capability to induce programmed cell death. AIF is the best characterised family member, while the information about AMID and AIFL is much scarcer. Nonetheless, available data support different roles as well as mechanisms of action of their particular apoptogenic and redox domains regarding both pro‐apoptotic and anti‐apoptotic activities. Moreover, diverse cellular functions, to date far from fully clarified, are envisaged for the transcripts corresponding to these three proteins. Here, we review the so far available knowledge on the moonlighting human AIF family from their molecular properties to their relevance in health and disease, through the evaluation of their potential cell death and redox functions in their different subcellular locations. This picture emerging from the current knowledge of the AIF family envisages its contribution to regulate signalling and transcription machineries in the crosstalk among mitochondria, the cytoplasm and the nucleus.

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Section: The Mitochondrial Pro‐life Roles Of the Aif Familymentioning

confidence: 97%

Section: The Aif Family In Health and Diseasementioning

confidence: 99%

The apoptosis‐inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei

2020

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“…Moreover, this ubiquitously expressed protein across eukaryotes also plays a vital role in cell development and survival [ 2 ]. These survival functions rely on its FAD-dependent activities, which contribute to maintain the stability of the mitochondrial electron transfer chain, supercomplex organization, and transmembrane potential, as well as to control mitochondrial reactive oxygen species (ROS) [ 3 ]. In healthy mitochondria, the hAIF is processed and the hAIF Δ 1-53 mature protein anchors in the inner membrane (IM)— via its N-terminal segment, facing the intermembrane space (IMS)— and folds in three domains ( Figure 1(a) ) [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

W196 and the β‐Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis‐Inducing Factor

Romero-Tamayo

Laplaza

Velázquez‐Campoy

et al. 2021

Oxidative Medicine and Cellular Longevity

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The human apoptosis-inducing factor (hAIF) is a moonlight flavoprotein involved in mitochondrial respiratory complex assembly and caspase-independent programmed cell death. These functions might be modulated by its redox-linked structural transition that enables hAIF to act as a NAD(H/+) redox sensor. Upon reduction with NADH, hAIF undergoes a conformational reorganization in two specific insertions—the flexible regulatory C-loop and the 190-202 β-harpin—promoting protein dimerization and the stabilization of a long-life charge transfer complex (CTC) that modulates its monomer-dimer equilibrium and its protein interaction network in healthy mitochondria. In this regard, here, we investigated the precise function of the β-hairpin in the AIF conformation landscape related to its redox mechanism, by analyzing the role played by W196, a key residue in the interaction of this motif with the regulatory C-loop. Mutations at W196 decrease the compactness and stability of the oxidized hAIF, indicating that the β-hairpin and C-loop coupling contribute to protein stability. Kinetic studies complemented with computational simulations reveal that W196 and the β-hairpin conformation modulate the low efficiency of hAIF as NADH oxidoreductase, contributing to configure its active site in a noncompetent geometry for hydride transfer and to stabilize the CTC state by enhancing the affinity for NAD+. Finally, the β-hairpin motif contributes to define the conformation of AIF’s interaction surfaces with its physiological partners. These findings improve our understanding on the molecular basis of hAIF’s cellular activities, a crucial aspect for clarifying its associated pathological mechanisms and developing new molecular therapies.

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“…However, it soon became clear that AIFM1 defects were related with a strong mitochondrial CI deficiency ( Vahsen et al, 2004 ; Bénit et al, 2008 ). Subsequent studies revealed that loss of AIFM1 function produced a more generalized combined respiratory chain deficiency in mouse and human cells ( Ghezzi et al, 2010 ; Delavallée et al, 2020 ), but the full ramifications of the AIFM1-CHCHD4 interaction remain to be resolved ( Reinhardt et al, 2020 ). More recently and using Drosophila melanogaster models, it was suggested that the dependency of CI biogenesis on AIFM1 was not direct but a consequence of decreased Mic19 levels instead ( Murari et al, 2020 ).…”

Section: Redox-regulation Of Oxphos Components and Biogenesis Factorsmentioning

confidence: 99%

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

Geldon

Fernández-Vizarra

Tokatlidis

2021

Front. Cell Dev. Biol.

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Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.

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Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus

Cited by 27 publications

References 90 publications

The apoptosis‐inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei

The apoptosis‐inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei

W196 and the β‐Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis‐Inducing Factor

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

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