Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2018 Apr 2

PMID 29605508

Citations 94

Authors

Daniele Bano

Jochen H M Prehn

Affiliations

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Abstract

Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms of onset, organ involvement and symptoms. Finally, we summarize how the study of AIFM1-linked pathologies may help to further expand our understanding of rare inherited forms of mitochondrial diseases.

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References

Ardissone A, Piscosquito G, Legati A, Langella T, Lamantea E, Garavaglia B . A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders. Neurology. 2015; 84(21):2193-5. PMC: 4451043. DOI: 10.1212/WNL.0000000000001613. View

Lin Y, Haynes C . Metabolism and the UPR(mt). Mol Cell. 2016; 61(5):677-682. PMC: 4779188. DOI: 10.1016/j.molcel.2016.02.004. View

Cheung E, Joza N, Steenaart N, McClellan K, Neuspiel M, McNamara S . Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. EMBO J. 2006; 25(17):4061-73. PMC: 1560366. DOI: 10.1038/sj.emboj.7601276. View

Alano C, Garnier P, Ying W, Higashi Y, Kauppinen T, Swanson R . NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci. 2010; 30(8):2967-78. PMC: 2864043. DOI: 10.1523/JNEUROSCI.5552-09.2010. View

Churbanova I, Sevrioukova I . Redox-dependent changes in molecular properties of mitochondrial apoptosis-inducing factor. J Biol Chem. 2008; 283(9):5622-31. DOI: 10.1074/jbc.M709147200. View

Curcio M, Salazar I, Mele M, Canzoniero L, Duarte C . Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury. Prog Neurobiol. 2016; 143:1-35. DOI: 10.1016/j.pneurobio.2016.06.001. View

Diodato D, Tasca G, Verrigni D, DAmico A, Rizza T, Tozzi G . A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease. Eur J Hum Genet. 2015; 24(3):463-6. PMC: 4755377. DOI: 10.1038/ejhg.2015.141. View

Germain M, Nguyen A, Khacho M, Patten D, Screaton R, Park D . LKB1-regulated adaptive mechanisms are essential for neuronal survival following mitochondrial dysfunction. Hum Mol Genet. 2012; 22(5):952-62. DOI: 10.1093/hmg/dds500. View

DiMauro S, Schon E, Carelli V, Hirano M . The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013; 9(8):429-44. PMC: 3959773. DOI: 10.1038/nrneurol.2013.126. View

10.

Andrabi S, Umanah G, Chang C, Stevens D, Karuppagounder S, Gagne J . Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A. 2014; 111(28):10209-14. PMC: 4104885. DOI: 10.1073/pnas.1405158111. View

11.

Rinaldi C, Grunseich C, Sevrioukova I, Schindler A, Horkayne-Szakaly I, Lamperti C . Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2012; 91(6):1095-102. PMC: 3516602. DOI: 10.1016/j.ajhg.2012.10.008. View

12.

Zong W, Rabinowitz J, White E . Mitochondria and Cancer. Mol Cell. 2016; 61(5):667-676. PMC: 4779192. DOI: 10.1016/j.molcel.2016.02.011. View

13.

Bano D, Ankarcrona M . Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences. Neurosci Lett. 2017; 663:79-85. DOI: 10.1016/j.neulet.2017.08.048. View

14.

Mierzewska H, Rydzanicz M, Bieganski T, Kosinska J, Mierzewska-Schmidt M, Lugowska A . Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease. Clin Genet. 2016; 91(1):30-37. DOI: 10.1111/cge.12792. View

15.

Cande C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C . AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene. 2004; 23(8):1514-21. DOI: 10.1038/sj.onc.1207279. View

16.

Wang W, Karamanlidis G, Tian R . Novel targets for mitochondrial medicine. Sci Transl Med. 2016; 8(326):326rv3. PMC: 4819426. DOI: 10.1126/scitranslmed.aac7410. View

17.

Perocchi F, Gohil V, Girgis H, Bao X, McCombs J, Palmer A . MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 2010; 467(7313):291-6. PMC: 2977980. DOI: 10.1038/nature09358. View

18.

Sevrioukova I . Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal. 2010; 14(12):2545-79. PMC: 3096518. DOI: 10.1089/ars.2010.3445. View

19.

Yuste V, Moubarak R, Delettre C, Bras M, Sancho P, Robert N . Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ. 2005; 12(11):1445-8. DOI: 10.1038/sj.cdd.4401687. View

20.

Vahsen N, Cande C, Briere J, Benit P, Joza N, Larochette N . AIF deficiency compromises oxidative phosphorylation. EMBO J. 2004; 23(23):4679-89. PMC: 533047. DOI: 10.1038/sj.emboj.7600461. View