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The disease is mainly caused by mutations in electron\u2010transfer flavoprotein dehydrogenase gene (<jats:italic>ETFDH<\/jats:italic>), which leads to decreased levels of ETF:QO in skeletal muscle. However, the specific underlying mechanisms triggering such degradation remain unknown. We constructed expression plasmids containing wild type ETF:QO and mutants ETF:QO\u2010A84T, R175H, A215T, Y333C, and cultured patient\u2010derived fibroblasts containing the following mutations in <jats:italic>ETFDH<\/jats:italic>: c.250G&gt;A (p.A84T), c.998A&gt;G (p.Y333C), c.770A&gt;G (p.Y257C), c.1254_1257delAACT (p. L418TfsX10), c.524G&gt;A (p.R175H), c.380T&gt;A (p.L127P), and c.892C&gt;T (p.P298S). We used in vitro expression systems and patient\u2010derived fibroblasts to detect stability of ETF:QO mutants then evaluated their interaction with Hsp70 interacting protein CHIP with active\/inactive ubiquitin E3 ligase carboxyl terminus using western blot and immunofluorescence staining. This interaction was confirmed in vitro and in vivo by co\u2010immunoprecipitation and immunofluorescence staining. We confirmed the existence two ubiquitination sites in mutant ETF:QO using mass spectrometry (MS) analysis. We found that mutant ETF:QO proteins were unstable and easily degraded in patient fibroblasts and in vitro expression systems by ubiquitin\u2010proteasome pathway, and identified the specific ubiquitin E3 ligase as CHIP, which forms complex to control mutant ETF:QO degradation through poly\u2010ubiquitination. CHIP\u2010dependent degradation of mutant ETF:QO proteins was confirmed by MS and site\u2010directed mutagenesis of ubiquitination sites. Hsp70 is directly involved in this process as molecular chaperone of CHIP. CHIP plays an important role in ubiquitin\u2010proteasome pathway dependent degradation of mutant ETF:QO by working as a chaperone\u2010assisted E3 ligase, which reveals CHIP's potential role in pathological mechanisms of late\u2010onset MADD.<\/jats:p>","DOI":"10.1002\/jimd.12361","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T10:42:35Z","timestamp":1610707355000},"page":"450-468","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>CHIP<\/scp> control degradation of mutant <scp>ETF<\/scp>:<scp>QO<\/scp> through ubiquitylation in late\u2010onset multiple <scp>acyl\u2010CoA<\/scp> dehydrogenase deficiency"],"prefix":"10.1002","volume":"44","author":[{"given":"Xin\u2010Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology Fujian Institute of Neurology, the First Affiliated Hospital, Fujian Medical University  Fuzhou Fujian 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