{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:40:04Z","timestamp":1785476404813,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T00:00:00Z","timestamp":1644969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The finding that the most common mitochondrial DNA mutation m.11778G&gt;A\/MT-ND4 (p.R340H) associated with Leber\u2019s hereditary optic neuropathy (LHON) induces rotenone resistance has produced a long-standing debate, because it contrasts structural evidence showing that the ND4 subunit is far away from the quinone-reaction site in complex I, where rotenone acts. However, recent cryo-electron microscopy data revealed that rotenone also binds to the ND4 subunit. We investigated the possible structural modifications induced by the LHON mutation and found that its amino acid replacement would disrupt a possible hydrogen bond between native R340 and Q139 in ND4, thereby destabilizing rotenone binding. Our analysis thus explains rotenone resistance in LHON patients as a biochemical signature of its pathogenic effect on complex I.<\/jats:p>","DOI":"10.3390\/molecules27041341","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T21:36:24Z","timestamp":1645047384000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New Insights on Rotenone Resistance of Complex I Induced by the m.11778G&gt;A\/MT-ND4 Mutation Associated with Leber\u2019s Hereditary Optic Neuropathy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0200-1712","authenticated-orcid":false,"given":"Francesco","family":"Musiani","sequence":"first","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie (FABIT), Universit\u00e0 di Bologna, I-40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rigobello","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie (FABIT), Universit\u00e0 di Bologna, I-40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Iommarini","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie (FABIT), Universit\u00e0 di Bologna, I-40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-6404","authenticated-orcid":false,"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Universit\u00e0 di Bologna, I-40100 Bologna, Italy"},{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, I-40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-119X","authenticated-orcid":false,"given":"Mauro","family":"Degli Esposti","sequence":"additional","affiliation":[{"name":"Center for Genomic Sciences, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Cuernavaca 62210, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0830-0000","authenticated-orcid":false,"given":"Anna Maria","family":"Ghelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie (FABIT), Universit\u00e0 di Bologna, I-40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"148153","DOI":"10.1016\/j.bbabio.2020.148153","article-title":"Respiratory complex I\u2014Mechanistic insights and advances in structure determination","volume":"1861","author":"Angerer","year":"2020","journal-title":"Biochim. 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