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Regardless of the initial injury, which could be toxic, mechanical, metabolic, or genetic, degeneration of axons shares a common mechanism involving mitochondrial dysfunction and production of reactive oxygen species. Critical steps in this degenerative process are still unknown. Here we show that calcium release from the axonal endoplasmic reticulum (ER) through ryanodine and IP<jats:sub>3<\/jats:sub>channels activates the mitochondrial permeability transition pore and contributes to axonal degeneration triggered by both mechanical and toxic insults in<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>mouse and rat model systems. These data reveal a critical and early ER-dependent step during axonal degeneration, providing novel targets for axonal protection in neurodegenerative conditions.<\/jats:p>","DOI":"10.1523\/jneurosci.4784-13.2014","type":"journal-article","created":{"date-parts":[[2014,5,21]],"date-time":"2014-05-21T17:05:00Z","timestamp":1400691900000},"page":"7179-7189","source":"Crossref","is-referenced-by-count":177,"title":["Calcium Release from Intra-Axonal Endoplasmic Reticulum Leads to Axon Degeneration through Mitochondrial Dysfunction"],"prefix":"10.1523","volume":"34","author":[{"given":"Rosario","family":"Villegas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas W.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Lillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillipe","family":"Pihan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery L.","family":"Twiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe A.","family":"Court","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2014,5,21]]},"reference":[{"key":"2023041304105900000_34.21.7179.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.08.056"},{"key":"2023041304105900000_34.21.7179.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098014"},{"key":"2023041304105900000_34.21.7179.3","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00083.2008"},{"key":"2023041304105900000_34.21.7179.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4065-10.2011"},{"key":"2023041304105900000_34.21.7179.5","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00095"},{"key":"2023041304105900000_34.21.7179.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2006.05213.x"},{"key":"2023041304105900000_34.21.7179.7","doi-asserted-by":"publisher","DOI":"10.1038\/361315a0"},{"key":"2023041304105900000_34.21.7179.8","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.1016\/S0021-9258(18)31518-7","article-title":"Identification of intracellular calcium pools. 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