{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T20:10:13Z","timestamp":1778184613893,"version":"3.51.4"},"posted":{"date-parts":[[2026,3,4]]},"group-title":"Cell Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"UNCF\/Bristol-Myers Squibb E.E. 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Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1\/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in\n                  <jats:italic>Drosophila<\/jats:italic>\n                  flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate\n                  <jats:italic>MFN2<\/jats:italic>\n                  expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.\n                <\/jats:p>","DOI":"10.64898\/2026.03.04.709625","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T08:56:03Z","timestamp":1772700963000},"source":"Crossref","is-referenced-by-count":0,"title":["Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication"],"prefix":"10.64898","author":[{"given":"Amber","family":"Crabtree","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"The Frist Center for Autism and Innovation, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suraj","family":"Thapliyal","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, AP, 517619, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohd Mabood","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"Department of Medicine, Division of Genetic Medicine & Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edgar Garza","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA"},{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Calixto Pablo Hernandez","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6809-9332","authenticated-orcid":false,"given":"Oleg","family":"Kovtun","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny 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Center, Nashville, TN 37232, USA"},{"name":"Department of Physiological Sciences, Pathology and Microbiology, HAND, research group, Mulungushi University School of Medicine and Health Sciences, Livingstone, Zambia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annet","family":"Kirabo","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"Department of Medicine, Division of Genetic Medicine & Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremiah","family":"Afolabi","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA"},{"name":"Department of Medicine, Division of Genetic Medicine & Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, 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