PMID- 38419397 OWN - NLM STAT- MEDLINE DCOM- 20240412 LR - 20240425 IS - 1097-4652 (Electronic) IS - 0021-9541 (Linking) VI - 239 IP - 4 DP - 2024 Apr TI - ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle. PG - e31204 LID - 10.1002/jcp.31204 [doi] AB - Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca(2+), lipid, and other metabolites between these organelles. 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-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, 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 Atf4 expression prevented the OPA1-loss-induced 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-dependent manner. CI - (c) 2024 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC. FAU - Hinton, Antentor Jr AU - Hinton A Jr AUID- ORCID: 0000-0002-7730-952X AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. FAU - Katti, Prasanna AU - Katti P AUID- ORCID: 0000-0002-6748-3460 AD - National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. FAU - Mungai, Margaret AU - Mungai M AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Hall, Duane D AU - Hall DD AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Koval, Olha AU - Koval O AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Shao, Jianqiang AU - Shao J AD - Central Microscopy Research Facility, Iowa City, Iowa, USA. FAU - Vue, Zer AU - Vue Z AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. FAU - Lopez, Edgar Garza AU - Lopez EG AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. FAU - Rostami, Rahmati AU - Rostami R AD - Department of Genetic Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, New York, USA. FAU - Neikirk, Kit AU - Neikirk K AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. FAU - Ponce, Jessica AU - Ponce J AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Streeter, Jennifer AU - Streeter J AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Schickling, Brandon AU - Schickling B AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Department of Medicine, Duke University, Durham, North Carolina, USA. FAU - Bacevac, Serif AU - Bacevac S AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Grueter, Chad AU - Grueter C AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Marshall, Andrea AU - Marshall A AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. FAU - Beasley, Heather K AU - Beasley HK AD - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA. FAU - Do Koo, Young AU - Do Koo Y AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Bodine, Sue C AU - Bodine SC AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. AD - Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. FAU - Nava, Nayeli G Reyes AU - Nava NGR AD - Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, USA. FAU - Quintana, Anita M AU - Quintana AM AD - Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, USA. FAU - Song, Long-Sheng AU - Song LS AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Grumbach, Isabella M AU - Grumbach IM AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Pereira, Renata O AU - Pereira RO AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. FAU - Glancy, Brian AU - Glancy B AD - National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Abel, E Dale AU - Abel ED AUID- ORCID: 0000-0001-5290-0738 AD - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. AD - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA. AD - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. LA - eng GR - R01 DK125405/DK/NIDDK NIH HHS/United States GR - AR/NIAMS NIH HHS/United States GR - T32 5T32GM133353/GF/NIH HHS/United States GR - NH/NIH HHS/United States PT - Journal Article DEP - 20240228 PL - United States TA - J Cell Physiol JT - Journal of cellular physiology JID - 0050222 RN - 145891-90-3 (Activating Transcription Factor 4) RN - SY7Q814VUP (Calcium) RN - 0 (Lipids) RN - 0 (Atf4 protein, mouse) RN - EC 3.6.1.- (Opa1 protein, mouse) RN - EC 3.6.1.- (GTP Phosphohydrolases) SB - IM MH - Animals MH - Mice MH - *Activating Transcription Factor 4/genetics/metabolism MH - Calcium/metabolism MH - Endoplasmic Reticulum/metabolism MH - Endoplasmic Reticulum Stress/genetics MH - Lipids MH - Mitochondria/metabolism MH - Muscle, Skeletal/metabolism MH - *Neurodegenerative Diseases/pathology MH - Male MH - Mice, Inbred C57BL MH - Cells, Cultured MH - GTP Phosphohydrolases/metabolism OTO - NOTNLM OT - activating transcription factor 4 OT - endoplasmic reticulum OT - integrated stress response OT - interorganelle communication OT - mitochondria EDAT- 2024/02/29 06:42 MHDA- 2024/04/12 06:44 CRDT- 2024/02/29 02:13 PHST- 2023/12/15 00:00 [revised] PHST- 2023/10/27 00:00 [received] PHST- 2024/01/16 00:00 [accepted] PHST- 2024/04/12 06:44 [medline] PHST- 2024/02/29 06:42 [pubmed] PHST- 2024/02/29 02:13 [entrez] AID - 10.1002/jcp.31204 [doi] PST - ppublish SO - J Cell Physiol. 2024 Apr;239(4):e31204. doi: 10.1002/jcp.31204. Epub 2024 Feb 28.