{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T13:31:48Z","timestamp":1779111108082,"version":"3.51.4"},"reference-count":58,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare, orphan autosomal recessive disorder caused by mutations in ferredoxin\u20102 (FDX2), which is a [2Fe\u20102S] cluster\u2010binding protein participating in the formation of iron\u2013sulfur clusters in mitochondria. In this biosynthetic pathway, FDX2 works as electron donor to promote the assembly of both [2Fe\u20102S] and [4Fe\u20104S] clusters. A recently identified missense mutation of MEOAL is the homozygous mutation c.431C&gt;T (p.P144L) described in six patients from two unrelated families. This mutation alters a highly conserved proline residue located in a loop of FDX2 that is distant from the [2Fe\u20102S] cluster. How this Pro to Leu substitution damages iron\u2013sulfur cluster biosynthesis is unknown. In this work, we have first compared the structural, dynamic, cluster binding and redox properties of WT and P144L [2Fe\u20102S] FDX2 to have clues on how the pathogenic P144L mutation can perturb the FDX2 function. Then, we have investigated the interaction of both WT and P144L [2Fe\u20102S] FDX2 with its physiological electron donor, ferredoxin reductase FDXR, comparing their electron transfer efficiency and protein\u2013protein recognition patterns. Overall, the data indicate that the pathogenic P144L mutation negatively affects the FDXR\u2010dependent electron transfer pathway from NADPH to FDX2, thereby reducing the capacity of FDX2 in assembling both [2Fe\u20102S] and [4Fe\u20104S] clusters. Our study also provided solid molecular evidences on the functional role of the C\u2010terminal tail of FDX2 in the electron transfer between FDX2 and FDXR.<\/jats:p>","DOI":"10.1002\/pro.5197","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T18:59:33Z","timestamp":1730141973000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the <scp>P144L<\/scp> mutation of <scp>FDX2<\/scp>"],"prefix":"10.1002","volume":"33","author":[{"given":"Deborah","family":"Grifagni","sequence":"first","affiliation":[{"name":"Magnetic Resonance Center CERM University of Florence  Florence Italy"},{"name":"Department of Chemistry University of Florence  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Doni","sequence":"additional","affiliation":[{"name":"Department of 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