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Mechanistically, NEDD4L disrupts mitochondrial function by binding to lipoyl(octanoyl) transferase 2 (LIPT2) and promoting its degradation through ubiquitination and lysosomal pathways. This process impairs lipoic acid biosynthesis and the lipoylation of E2 subunits of alpha-ketoglutarate dehydrogenase (\u03b1-KGDH E2). Furthermore, either overexpressing LIPT2 or administering lipoic acid mitigates neurodegeneration and rectifies deficits in motor coordination activity. These findings unveil a molecular mechanism underlying the regulation of lipoic acid metabolism and underscore the potential therapeutic role of protein lipoylation in the treatment of HD.<\/jats:p>","DOI":"10.1073\/pnas.2503342122","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T17:45:22Z","timestamp":1752601522000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in Huntington\u2019s disease"],"prefix":"10.1073","volume":"122","author":[{"given":"Pan","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of 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