{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:04:06Z","timestamp":1791295446321,"version":"4.1.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2015,7,9]],"date-time":"2015-07-09T00:00:00Z","timestamp":1436400000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,7,9]],"date-time":"2015-07-09T00:00:00Z","timestamp":1436400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in the <jats:italic>AIFM1<\/jats:italic> gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities and progressive mitochondrial encephalomyopathies. In humans, rodents and invertebrates, AIF deficiency results in loss of respiratory complexes and, therefore, impaired OXPHOS. The molecular mechanisms underlying AIF-induced mitochondrial dysfunction remain elusive. Here we show that AIF physically interacts with the oxidoreductase CHCHD4\/MIA40. In patient-derived fibroblasts as well as in tissues and glia cells from Harlequin (Hq) mutant mice, AIF deficiency correlates with decreased MIA40 protein levels, without affecting mRNA transcription. Importantly, MIA40 overexpression counteracts loss of respiratory subunits in Hq cells. Together, our findings suggest that MIA40 reduction contributes to the effects of AIF deficiency on OXPHOS, as it may impact on the correct assembly and maintenance of the respiratory subunits. This may be relevant for the development of new therapeutic approaches for AIF-related mitochondrial disorders.<\/jats:p>","DOI":"10.1038\/cddis.2015.170","type":"journal-article","created":{"date-parts":[[2015,7,9]],"date-time":"2015-07-09T12:44:42Z","timestamp":1436445882000},"page":"e1814-e1814","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Loss of apoptosis-inducing factor critically affects MIA40 function"],"prefix":"10.1038","volume":"6","author":[{"given":"K","family":"Meyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Buettner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Zeviani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Bano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Nicotera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,9]]},"reference":[{"key":"BFcddis2015170_CR1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/17135","volume":"397","author":"SA Susin","year":"1999","unstructured":"Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441\u2013446.","journal-title":"Nature"},{"key":"BFcddis2015170_CR2","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1084\/jem.184.4.1331","volume":"184","author":"SA Susin","year":"1996","unstructured":"Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A et al. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 1996; 184: 1331\u20131341.","journal-title":"J Exp Med"},{"key":"BFcddis2015170_CR3","doi-asserted-by":"publisher","first-page":"e00021","DOI":"10.1042\/AN20090046","volume":"1","author":"SW Yu","year":"2009","unstructured":"Yu SW, Wang Y, Frydenlund DS, Ottersen OP, Dawson VL, Dawson TM . Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release. ASN Neuro 2009; 1: e00021.","journal-title":"ASN Neuro"},{"key":"BFcddis2015170_CR4","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1126\/science.1230593","volume":"339","author":"HW Rhee","year":"2013","unstructured":"Rhee HW, Zou P, Udeshi ND, Martell JD, Mootha VK, Carr SA et al. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science 2013; 339: 1328\u20131331.","journal-title":"Science"},{"key":"BFcddis2015170_CR5","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1089\/ars.2010.3445","volume":"14","author":"IF Sevrioukova","year":"2011","unstructured":"Sevrioukova IF . Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal 2011; 14: 2545\u20132579.","journal-title":"Antioxid Redox Signal"},{"key":"BFcddis2015170_CR6","doi-asserted-by":"publisher","first-page":"4679","DOI":"10.1038\/sj.emboj.7600461","volume":"23","author":"N Vahsen","year":"2004","unstructured":"Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N et al. AIF deficiency compromises oxidative phosphorylation. EMBO J 2004; 23: 4679\u20134689.","journal-title":"EMBO J"},{"key":"BFcddis2015170_CR7","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/j.cell.2007.08.047","volume":"131","author":"JA Pospisilik","year":"2007","unstructured":"Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 2007; 131: 476\u2013491.","journal-title":"Cell"},{"key":"BFcddis2015170_CR8","doi-asserted-by":"publisher","first-page":"9918","DOI":"10.1073\/pnas.0603950103","volume":"103","author":"D Brown","year":"2006","unstructured":"Brown D, Yu BD, Joza N, Benit P, Meneses J, Firpo M et al. Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc Natl Acad Sci USA 2006; 103: 9918\u20139923.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015170_CR9","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/nature01034","volume":"419","author":"JA Klein","year":"2002","unstructured":"Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 2002; 419: 367\u2013374.","journal-title":"Nature"},{"key":"BFcddis2015170_CR10","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1097\/NEN.0b013e318148b822","volume":"66","author":"V El Ghouzzi","year":"2007","unstructured":"El Ghouzzi V, Csaba Z, Olivier P, Lelouvier B, Schwendimann L, Dournaud P et al. Apoptosis-inducing factor deficiency induces early mitochondrial degeneration in brain followed by progressive multifocal neuropathology. J Neuropathol Exp Neurol 2007; 66: 838\u2013847.","journal-title":"J Neuropathol Exp Neurol"},{"key":"BFcddis2015170_CR11","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1016\/j.ajhg.2012.10.008","volume":"91","author":"C Rinaldi","year":"2012","unstructured":"Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C et al. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet 2012; 91: 1095\u20131102.","journal-title":"Am J Hum Genet"},{"key":"BFcddis2015170_CR12","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.ajhg.2010.03.002","volume":"86","author":"D Ghezzi","year":"2010","unstructured":"Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P et al. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet 2010; 86: 639\u2013649.","journal-title":"Am J Hum Genet"},{"key":"BFcddis2015170_CR13","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.ymgme.2011.09.020","volume":"104","author":"I Berger","year":"2011","unstructured":"Berger I, Ben-Neriah Z, Dor-Wolman T, Shaag A, Saada A, Zenvirt S et al. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Mol Genet Metab 2011; 104: 517\u2013520.","journal-title":"Mol Genet Metab"},{"key":"BFcddis2015170_CR14","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.mito.2015.01.001","volume":"21","author":"M Kettwig","year":"2015","unstructured":"Kettwig M, Schubach M, Zimmermann FA, Klinge L, Mayr JA, Biskup S et al. From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. Mitochondrion 2015; 21: 12\u201318.","journal-title":"Mitochondrion"},{"key":"BFcddis2015170_CR15","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1212\/WNL.0000000000001613","volume":"84","author":"A Ardissone","year":"2015","unstructured":"Ardissone A, Piscosquito G, Legati A, Langella T, Lamantea E, Garavaglia B et al. A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders. Neurology 2015; 84: 2193\u20132195.","journal-title":"Neurology"},{"key":"BFcddis2015170_CR16","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nrneurol.2013.126","volume":"9","author":"S DiMauro","year":"2013","unstructured":"DiMauro S, Schon EA, Carelli V, Hirano M . The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013; 9: 429\u2013444.","journal-title":"Nat Rev Neurol"},{"key":"BFcddis2015170_CR17","doi-asserted-by":"publisher","first-page":"2656","DOI":"10.1056\/NEJMra022567","volume":"348","author":"S DiMauro","year":"2003","unstructured":"DiMauro S, Schon EA . Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348: 2656\u20132668.","journal-title":"N Engl J Med"},{"key":"BFcddis2015170_CR18","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1038\/nrneurol.2013.129","volume":"9","author":"G Pfeffer","year":"2013","unstructured":"Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol 2013; 9: 474\u2013481.","journal-title":"Nat Rev Neurol"},{"key":"BFcddis2015170_CR19","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/cdd.2008.24","volume":"15","author":"N Joza","year":"2008","unstructured":"Joza N, Galindo K, Pospisilik JA, Benit P, Rangachari M, Kanitz EE et al. The molecular archaeology of a mitochondrial death effector: AIF in Drosophila. Cell Death Differ 2008; 15: 1009\u20131018.","journal-title":"Cell Death Differ"},{"key":"BFcddis2015170_CR20","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1126\/science.1181348","volume":"328","author":"JR Hutchins","year":"2010","unstructured":"Hutchins JR, Toyoda Y, Hegemann B, Poser I, Heriche JK, Sykora MM et al. Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science 2010; 328: 593\u2013599.","journal-title":"Science"},{"key":"BFcddis2015170_CR21","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1016\/j.cell.2012.08.011","volume":"150","author":"PC Havugimana","year":"2012","unstructured":"Havugimana PC, Hart GT, Nepusz T, Yang H, Turinsky AL, Li Z et al. A census of human soluble protein complexes. Cell 2012; 150: 1068\u20131081.","journal-title":"Cell"},{"key":"BFcddis2015170_CR22","doi-asserted-by":"publisher","first-page":"3735","DOI":"10.1038\/sj.emboj.7600389","volume":"23","author":"A Chacinska","year":"2004","unstructured":"Chacinska A, Pfannschmidt S, Wiedemann N, Kozjak V, Sanjuan Szklarz LK, Schulze-Specking A et al. Essential role of Mia40 in import and assembly of mitochondrial intermembrane space proteins. EMBO J 2004; 23: 3735\u20133746.","journal-title":"EMBO J"},{"key":"BFcddis2015170_CR23","doi-asserted-by":"publisher","first-page":"2459","DOI":"10.1039\/c0mb00058b","volume":"6","author":"G Cavallaro","year":"2010","unstructured":"Cavallaro G . Genome-wide analysis of eukaryotic twin CX9C proteins. Mol Biosyst 2010; 6: 2459\u20132470.","journal-title":"Mol Biosyst"},{"key":"BFcddis2015170_CR24","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1091\/mbc.e12-12-0862","volume":"24","author":"M Fischer","year":"2013","unstructured":"Fischer M, Horn S, Belkacemi A, Kojer K, Petrungaro C, Habich M et al. Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells. Mol Biol Cell 2013; 24: 2160\u20132170.","journal-title":"Mol Biol Cell"},{"key":"BFcddis2015170_CR25","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.ajhg.2009.04.004","volume":"84","author":"A Di Fonzo","year":"2009","unstructured":"Di Fonzo A, Ronchi D, Lodi T, Fassone E, Tigano M, Lamperti C et al. The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am J Hum Genet 2009; 84: 594\u2013604.","journal-title":"Am J Hum Genet"},{"key":"BFcddis2015170_CR26","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/sj.emboj.7600614","volume":"24","author":"H Otera","year":"2005","unstructured":"Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K . Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 2005; 24: 1375\u20131386.","journal-title":"EMBO J"},{"key":"BFcddis2015170_CR27","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.tibs.2009.12.008","volume":"35","author":"E Hangen","year":"2010","unstructured":"Hangen E, Blomgren K, Benit P, Kroemer G, Modjtahedi N . Life with or without AIF. Trends Biochem Sci 2010; 35: 278\u2013287.","journal-title":"Trends Biochem Sci"},{"key":"BFcddis2015170_CR28","doi-asserted-by":"publisher","first-page":"5622","DOI":"10.1074\/jbc.M709147200","volume":"283","author":"IY Churbanova","year":"2008","unstructured":"Churbanova IY, Sevrioukova IF . Redox-dependent changes in molecular properties of mitochondrial apoptosis-inducing factor. J Biol Chem 2008; 283: 5622\u20135631.","journal-title":"J Biol Chem"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2015170.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015170","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015170.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T10:07:26Z","timestamp":1672913246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2015170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,9]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2015,7]]}},"alternative-id":["BFcddis2015170"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2015.170","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,9]]},"assertion":[{"value":"12 May 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}