ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

Antentor Hinton Jr; Prasanna Katti; Margaret Mungai; Duane D Hall; Olha Koval; Jianqiang Shao; Zer Vue; Edgar Garza Lopez; Rahmati Rostami; Kit Neikirk; Jessica Ponce; Jennifer Streeter; Brandon Schickling; Serif Bacevac; Chad Grueter; Andrea Marshall; Heather K Beasley; Young Do Koo; Sue C Bodine; Nayeli G Reyes Nava; Anita M Quintana; Long-Sheng Song; Isabella M Grumbach; Renata O Pereira; Brian Glancy; E Dale Abel

doi:10.1002/jcp.31204

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ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

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ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

Antentor Hinton Jr, Prasanna Katti, Margaret Mungai, Duane D Hall, Olha Koval, Jianqiang Shao, Zer Vue, Edgar Garza Lopez, Rahmati Rostami, Kit Neikirk, …

Journal of cellular physiology, Vol.239(4), e31204

04/11/2024

DOI: 10.1002/jcp.31204

PMCID: PMC11144302

PMID: 38419397

Appears in UI Libraries Support Open Access

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Abstract

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 , 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.

interorganelle communication

mitochondria

endoplasmic reticulum

activating transcription factor 4

integrated stress response

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Details

Title: Subtitle: ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle
Creators: Antentor Hinton Jr - Vanderbilt University
Prasanna Katti - National Heart Lung and Blood Institute
Margaret Mungai - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Duane D Hall - University of Iowa
Olha Koval - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Jianqiang Shao - Central Microscopy Research Facility, Iowa City, Iowa, USA
Zer Vue - Vanderbilt University
Edgar Garza Lopez - Department of Internal Medicine, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Rahmati Rostami - Cornell University
Kit Neikirk - Vanderbilt University
Jessica Ponce - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Jennifer Streeter - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Brandon Schickling - Duke University
Serif Bacevac - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Chad Grueter - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Andrea Marshall - Vanderbilt University
Heather K Beasley - Vanderbilt University
Young Do Koo - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Sue C Bodine - Oklahoma Medical Research Foundation
Nayeli G Reyes Nava - The University of Texas at El Paso
Anita M Quintana - The University of Texas at El Paso
Long-Sheng Song - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Isabella M Grumbach - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Renata O Pereira - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA
Brian Glancy - National Institute of Arthritis and Musculoskeletal and Skin Diseases
E Dale Abel - David Geffen School of Medicine at UCLA
Resource Type: Journal article
Publication Details: Journal of cellular physiology, Vol.239(4), e31204
DOI: 10.1002/jcp.31204
PMID: 38419397
PMCID: PMC11144302
NLM abbreviation: J Cell Physiol
eISSN: 1097-4652
Publisher: Wiley
Grant note: NIAMS NIH HHS T32 5T32GM133353 / NIH HHS NIH HHS
Language: English
Electronic publication date: 02/28/2024
Date published: 04/11/2024
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Craniofacial Anomalies Research Center; Obstetrics and Gynecology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984562589102771

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