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Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle\u2010specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin\u20102, a known MERC protein. In the present study, we tested the hypothesis that\n                    <jats:italic>Opa1<\/jats:italic>\n                    downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing\n                    <jats:italic>Atf4<\/jats:italic>\n                    expression prevented the OPA1\u2010loss\u2010induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4\u2010dependent manner.\n                  <\/jats:p>","DOI":"10.1002\/jcp.31204","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T02:05:03Z","timestamp":1709172303000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["ATF4\u2010dependent increase in mitochondrial\u2010endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle"],"prefix":"10.1002","volume":"239","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-952X","authenticated-orcid":false,"suffix":"Jr.","given":"Antentor","family":"Hinton","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City Iowa USA"},{"name":"Fraternal Order of Eagles Diabetes Research Center Iowa City Iowa USA"},{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6748-3460","authenticated-orcid":false,"given":"Prasanna","family":"Katti","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Mungai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City Iowa USA"},{"name":"Fraternal Order of Eagles Diabetes Research Center Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane D.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olha","family":"Koval","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City Iowa USA"},{"name":"Fraternal Order of Eagles Diabetes Research Center Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Shao","sequence":"additional","affiliation":[{"name":"Central Microscopy Research Facility Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zer","family":"Vue","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar Garza","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmati","family":"Rostami","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine Joan &amp; Sanford I. 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