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Despite the identification of the involvement of PSEN in Alzheimer\u2019s Disease (AD) \u223c20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, \u03b3-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.<\/jats:p>","DOI":"10.1534\/genetics.115.182808","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T02:48:10Z","timestamp":1445654890000},"page":"1453-1466","source":"Crossref","is-referenced-by-count":66,"title":["A \u03b3-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in <i>Caenorhabditis elegans<\/i>"],"prefix":"10.1093","volume":"201","author":[{"given":"Shaarika","family":"Sarasija","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth R","family":"Norman","sequence":"additional","affiliation":[{"name":"Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,10,21]]},"reference":[{"key":"2022011310115616000_bib1"},{"key":"2022011310115616000_bib78"},{"issue":"Pt 24","key":"2022011310115616000_bib2","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1242\/jcs.111.24.3645","article-title":"The presenilin protein family member SPE-4 localizes to an ER\/Golgi derived organelle and is required for proper cytoplasmic partitioning during Caenorhabditis elegans spermatogenesis.","volume":"111","author":"Arduengo","year":"1998","journal-title":"J. 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