The molecular role of Sigmar1 in regulating mitochondrial function through mitochondrial localization in cardiomyocytes.

Animals Energy Metabolism / physiology Female Gene Knockdown Techniques HEK293 Cells Humans Male Mice Mitochondria, Heart / physiology Myocytes, Cardiac / metabolism Protein Transport / physiology RNA, Small Interfering Rats Receptors, sigma / genetics Sigma-1 Receptor
Cardiomyocytes Mitochondria Sigmar1 Subcellular localization

Journal

Mitochondrion
ISSN: 1872-8278
Titre abrégé: Mitochondrion
Pays: Netherlands
ID NLM: 100968751

Informations de publication

Date de publication:
01 2022
Historique:
received: 13 08 2021
revised: 02 12 2021
accepted: 06 12 2021
pubmed: 14 12 2021
medline: 24 3 2022
entrez: 13 12 2021
Statut: ppublish

Résumé

Sigmar1 is a widely expressed molecular chaperone protein in mammalian cell systems. Accumulating research demonstrated the cardioprotective roles of pharmacologic Sigmar1 activation by ligands in preclinical rodent models of cardiac injury. Extensive biochemical and immuno-electron microscopic research demonstrated Sigmar1's sub-cellular localization largely depends on cell and organ types. Despite comprehensive studies, Sigmar1's direct molecular role in cardiomyocytes remains elusive. In the present study, we determined Sigmar1's subcellular localization, transmembrane topology, and function using complementary microscopy, biochemical, and functional assays in cardiomyocytes. Quantum dots in transmission electron microscopy showed Sigmar1 labeled quantum dots on the mitochondrial membranes, lysosomes, and sarcoplasmic reticulum-mitochondrial interface. Subcellular fractionation of heart cell lysates confirmed Sigmar1's localization in purified mitochondria fraction and lysosome fraction. Immunocytochemistry confirmed Sigmar1 colocalization with mitochondrial proteins in isolated adult mouse cardiomyocytes. Sigmar1's mitochondrial localization was further confirmed by Sigmar1 colocalization with Mito-Tracker in isolated mouse heart mitochondria. A series of biochemical experiments, including alkaline extraction and proteinase K treatment of purified heart mitochondria, demonstrated Sigmar1 as an integral mitochondrial membrane protein. Sigmar1's structural requirement for mitochondrial localization was determined by expressing FLAG-tagged Sigmar1 fragments in cells. Full-length Sigmar1 and Sigmar1's C terminal-deletion fragments were able to localize to the mitochondrial membrane, whereas N-terminal deletion fragment was unable to incorporate into the mitochondria. Finally, functional assays using extracellular flux analyzer and high-resolution respirometry showed Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes. Overall, we found that Sigmar1 localizes to mitochondrial membranes and is indispensable for maintaining mitochondrial respiratory homeostasis in cardiomyocytes.

Identifiants

DOI: 10.1016/j.mito.2021.12.002 PMID: 34902622 PMC: PMC8790786
pubmed: 34902622
pii: S1567-7249(21)00169-0
doi: 10.1016/j.mito.2021.12.002
pmc: PMC8790786
mid: NIHMS1765001
pii:
doi:

Substances chimiques

RNA, Small Interfering 0
Receptors, sigma 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

159-175

Subventions

Organisme : NIAAA NIH HHS
ID : R21 AA026708
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL122354
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL152723
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121307
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL098435
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133497
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL149264
Pays : United States
Organisme : NHLBI NIH HHS
ID : R15 HL141998
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145753
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141155
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA025744
Pays : United States

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

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Auteurs

Chowdhury S Abdullah (CS)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Richa Aishwarya (R)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Shafiul Alam (S)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Naznin Sultana Remex (NS)

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Mahboob Morshed (M)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Sadia Nitu (S)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Sumitra Miriyala (S)

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Manikandan Panchatcharam (M)

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Brandon Hartman (B)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Judy King (J)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Mohammad Alfrad Nobel Bhuiyan (M)

Department of Medicine, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

James Traylor (J)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Christopher G Kevil (CG)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

A Wayne Orr (AW)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.

Md Shenuarin Bhuiyan (MS)

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA. Electronic address: shenu.bhuiyan@lsuhs.edu.

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