{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:55:20Z","timestamp":1790740520194,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>Sustained c\u2010Jun N\u2010terminal kinase (JNK) activation has been implicated in many models of cell death and tissue injury. Phosphorylated JNK (p\u2010JNK) interacts with the mitochondrial outer membrane SH3 homology associated BTK binding protein (Sab, or SH3BP5). Using knockdown or liver\u2010specific deletion of Sab, we aimed to elucidate the consequences of this interaction on mitochondrial function in isolated mitochondria and liver injury models <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. Respiration in isolated mitochondria was directly inhibited by p\u2010JNK + adenosine triphosphate. Knockdown or liver\u2010specific knockout of Sab abrogated this effect and markedly inhibited sustained JNK activation and liver injury from acetaminophen or tumor necrosis factor\/galactosamine. We then elucidated an intramitochondrial pathway in which interaction of JNK and Sab on the outside of the mitochondria released protein tyrosine phosphatase, nonreceptor type 6 (SHP1, or PTPN6) from Sab in the inside of the mitochondrial outer membrane, leading to its activation and transfer to the inner membrane, where it dephosphorylates P\u2010Y419Src (active), which required a platform protein, docking protein 4 (DOK4), on the inner membrane. Knockdown of mitochondrial DOK4 or SHP1 inhibited the inactivation of mitochondrial p\u2010Src and the effect of p\u2010JNK on mitochondria. <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic> The binding to and phosphorylation of Sab by p\u2010JNK on the outer mitochondrial membrane leads to SHP1\u2010dependent and DOK4\u2010dependent inactivation of p\u2010Src on the inner membrane; inactivation of mitochondrial Src inhibits electron transport and increases reactive oxygen species release, which sustains JNK activation and promotes cell death and organ injury. (H<jats:sc>epatology<\/jats:sc> 2016;63:1987\u20102003)<\/jats:p>","DOI":"10.1002\/hep.28486","type":"journal-article","created":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T23:28:11Z","timestamp":1454628491000},"page":"1987-2003","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":167,"title":["c\u2010Jun N\u2010terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)\u2010dependent pathway leading to inactivation of intramitochondrial Src"],"prefix":"10.1097","volume":"63","author":[{"given":"Sanda","family":"Win","sequence":"first","affiliation":[{"name":"Research Center for Liver Diseases, Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin Aung","family":"Than","sequence":"additional","affiliation":[{"name":"Research Center for Liver Diseases, Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Win Maw","family":"Min","sequence":"additional","affiliation":[{"name":"Research Center for Liver Diseases, Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Aghajan","sequence":"additional","affiliation":[{"name":"IONIS Pharmaceuticals,Carlsbad,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Kaplowitz","sequence":"additional","affiliation":[{"name":"Research Center for Liver Diseases, Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,3,15]]},"reference":[{"key":"hep28486-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK: signaling in 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