{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:47:03Z","timestamp":1791298023797,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2008,12,9]],"date-time":"2008-12-09T00:00:00Z","timestamp":1228780800000},"content-version":"vor","delay-in-days":38,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2008,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>There are marked mitochondrial abnormalities in <jats:italic>parkin<\/jats:italic>\u2010knock\u2010out <jats:italic>Drosophila<\/jats:italic> and other model systems. The aim of our study was to determine mitochondrial function and morphology in <jats:italic>parkin<\/jats:italic>\u2010mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in <jats:italic>parkin<\/jats:italic>\u2010mutant human tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous <jats:italic>parkin<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Parkin<\/jats:italic>\u2010mutant cells had lower mitochondrial complex I activity and complex I\u2013linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of <jats:italic>parkin<\/jats:italic> in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of <jats:italic>parkin,<\/jats:italic> mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study demonstrates marked abnormalities of mitochondrial function and morphology in <jats:italic>parkin<\/jats:italic>\u2010mutant patients and provides proof\u2010of\u2010principle data for the potential usefulness of this new model system as a tool to screen for disease\u2010modifying compounds in genetically homogenous parkinsonian disorders. Ann Neurol 2008;64:555\u2013565<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21492","type":"journal-article","created":{"date-parts":[[2008,12,10]],"date-time":"2008-12-10T01:06:25Z","timestamp":1228871185000},"page":"555-565","source":"Crossref","is-referenced-by-count":322,"title":["Mitochondrial function and morphology are impaired in <i>parkin<\/i>\u2010mutant fibroblasts"],"prefix":"10.1002","volume":"64","author":[{"given":"Heather","family":"Mortiboys","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly Jean","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner J. 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