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Here, for the first time, we show that Zdhhc13 plays a key role in anxiety-related behaviors and motor function, as well as brain bioenergetics, in a mouse model (<jats:italic>luc<\/jats:italic>) carrying a spontaneous<jats:italic>Zdhhc13<\/jats:italic>recessive mutation. At 3\u2009m of age, mutant mice displayed increased sensorimotor gating, anxiety, hypoactivity, and decreased motor coordination, compared to littermate controls. Loss of Zdhhc13 in cortex and cerebellum from 3- and 24\u2009m old hetero- and homozygous male mutant mice resulted in lower levels of Drp1<jats:italic>S-<\/jats:italic>palmitoylation accompanied by altered mitochondrial dynamics, increased glycolysis, glutaminolysis and lactic acidosis, and neurotransmitter imbalances. Employing<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>models, we identified that Zdhhc13-dependent Drp1<jats:italic>S<\/jats:italic>-palmitoylation, which acting alone or in concert, enables the normal occurrence of the fission-fusion process.<jats:italic>In vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>direct Zdhhc13-Drp1 protein interaction was observed, confirming Drp1 as a substrate of Zdhhc13. Abnormal fission-fusion processes result in disrupted mitochondria morphology and distribution affecting not only mitochondrial ATP output but neurotransmission and integrity of synaptic structures in the brain, setting the basis for the behavioral abnormalities described in the<jats:italic>Zdhhc13<\/jats:italic>-deficient mice.<\/jats:p>","DOI":"10.1038\/s41598-017-12889-0","type":"journal-article","created":{"date-parts":[[2017,10,4]],"date-time":"2017-10-04T06:55:33Z","timestamp":1507100133000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills"],"prefix":"10.1038","volume":"7","author":[{"given":"Eleonora","family":"Napoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8841-7219","authenticated-orcid":false,"given":"Alexsandra","family":"Espejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos J.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Benavides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1033-7435","authenticated-orcid":false,"given":"Cecilia","family":"Giulivi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,16]]},"reference":[{"key":"12889_CR1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1080\/09687680802646703","volume":"26","author":"SL Planey","year":"2009","unstructured":"Planey, S. 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