{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T06:25:56Z","timestamp":1783751156705,"version":"3.55.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG059721"],"award-info":[{"award-number":["R01AG059721"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1NS122218"],"award-info":[{"award-number":["RF1NS122218"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG067741"],"award-info":[{"award-number":["R01AG067741"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Accumulating toxic protein assemblies, including A\u03b2 and tau, and dysfunctional mitochondria are associated with synaptic and neuronal loss in Alzheimer\u2019s disease (AD). Such accumulations are thought to be owing to clearance defects in the autophagy-lysosome pathway. Mitochondrial dysfunction is evident in AD brains and animal models at multiple levels, such as mitochondrial genomic mutations, disrupted bioenergetics, deregulated mitochondrial dynamics and impaired clearance of damaged mitochondria (mitophagy). Slingshot homolog-1 (SSH1) is a phosphatase activated by oxidative stress, high intracellular levels of Ca2+ and A\u03b242 oligomers (A\u03b242O), known for its function to dephosphorylate\/activate cofilin through the N-terminal region. SSH1-mediated cofilin dephosphorylation results in Ab42O-induced severing of F-actin and translocation of cofilin to mitochondria, which promotes mitochondria-mediated apoptosis, synaptic loss and synaptic deficits. On the other hand, SSH1-mediated dephosphorylation\/deactivation of the autophagy-cargo receptor p62 (SQSTM1), through its C-terminal region, inhibits p62 autophagy flux. However, the interplay between these two different activities of SSH1 in A\u03b242O-induced mitochondrial toxicity remains unclear. In this study, we assessed the role of endogenous SSH1 and different regions of SSH1 in regulating mitochondrial health, mitochondrial respiration, clearance of damaged mitochondria and synaptic integrity in vitro and in vivo. Our results indicate that SSH1 suppresses mitochondrial health and respiration through the cofilin-binding N-terminal region, whereas SSH1 impairs mitophagy through a newly identified ~\u2009100 residue p62-binding domain in the C-terminal region. These results indicate that both N-terminal and C-terminal regions negatively impact mitochondria by distinct and independent modalities to amplify mitochondrial abnormalities, making SSH1 an excellent target to mitigate AD pathogenesis.<\/jats:p>","DOI":"10.1093\/hmg\/ddad006","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T20:42:28Z","timestamp":1673469748000},"page":"1660-1672","source":"Crossref","is-referenced-by-count":9,"title":["Slingshot homolog-1 amplifies mitochondrial abnormalities by distinctly impairing health and clearance of mitochondria"],"prefix":"10.1093","volume":"32","author":[{"given":"Sara","family":"Cazzaro","sequence":"first","affiliation":[{"name":"Department of Pathology , School of Medicine, , Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University , School of Medicine, , Cleveland, OH 44106, USA"},{"name":"Department of Molecular Medicine, Byrd Alzheimer\u2019s Center & Research Institute, USF Health Morsani College of Medicine , Tampa, FL 33613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Byrd Alzheimer\u2019s Center & Research Institute, USF Health Morsani College of Medicine , Tampa, FL 33613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria K","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology , School of Medicine, , Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University , School of Medicine, , Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yenna K","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology , School of Medicine, , Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University , School of Medicine, , Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9194-1361","authenticated-orcid":false,"given":"Jung-A A","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Pathology , School of Medicine, , Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University , School of Medicine, , Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"2023050516333410300_ref1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3389\/fnagi.2019.00311","article-title":"Dysfunctional mitochondria and mitophagy as drivers of Alzheimer's disease pathogenesis","volume":"11","author":"Chakravorty","year":"2019","journal-title":"Front. 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