Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

Vernica Contreras-Shannon, Dylan L. Heart, R. Madelaine Paredes, Erica Navaira, Gabriel Catano, Shivani Kaushal Maffi, Consuelo Walss-Bass

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background: Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined. Methodology/Principal Findings: Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 μM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line. Conclusions/Significance: Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.

Original languageEnglish (US)
Article numbere59012
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 20 2013

Fingerprint

Mitochondria
Clozapine
metabolic syndrome
Encephalitis
encephalitis
Brain
mitochondria
insulin
Insulin
obesity
drugs
cells
inflammation
cell lines
Obesity
membrane potential
Cells
monocytes
Medical problems
Inflammation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Contreras-Shannon, V., Heart, D. L., Paredes, R. M., Navaira, E., Catano, G., Maffi, S. K., & Walss-Bass, C. (2013). Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells. PLoS One, 8(3), [e59012]. https://doi.org/10.1371/journal.pone.0059012

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells. / Contreras-Shannon, Vernica; Heart, Dylan L.; Paredes, R. Madelaine; Navaira, Erica; Catano, Gabriel; Maffi, Shivani Kaushal; Walss-Bass, Consuelo.

In: PLoS One, Vol. 8, No. 3, e59012, 20.03.2013.

Research output: Contribution to journalArticle

Contreras-Shannon, V, Heart, DL, Paredes, RM, Navaira, E, Catano, G, Maffi, SK & Walss-Bass, C 2013, 'Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells', PLoS One, vol. 8, no. 3, e59012. https://doi.org/10.1371/journal.pone.0059012
Contreras-Shannon V, Heart DL, Paredes RM, Navaira E, Catano G, Maffi SK et al. Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells. PLoS One. 2013 Mar 20;8(3). e59012. https://doi.org/10.1371/journal.pone.0059012
Contreras-Shannon, Vernica ; Heart, Dylan L. ; Paredes, R. Madelaine ; Navaira, Erica ; Catano, Gabriel ; Maffi, Shivani Kaushal ; Walss-Bass, Consuelo. / Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells. In: PLoS One. 2013 ; Vol. 8, No. 3.
@article{6d19c5be2bb04781b7dfbb1df06ec2de,
title = "Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells",
abstract = "Background: Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined. Methodology/Principal Findings: Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 μM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line. Conclusions/Significance: Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.",
author = "Vernica Contreras-Shannon and Heart, {Dylan L.} and Paredes, {R. Madelaine} and Erica Navaira and Gabriel Catano and Maffi, {Shivani Kaushal} and Consuelo Walss-Bass",
year = "2013",
month = "3",
day = "20",
doi = "10.1371/journal.pone.0059012",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

AU - Contreras-Shannon, Vernica

AU - Heart, Dylan L.

AU - Paredes, R. Madelaine

AU - Navaira, Erica

AU - Catano, Gabriel

AU - Maffi, Shivani Kaushal

AU - Walss-Bass, Consuelo

PY - 2013/3/20

Y1 - 2013/3/20

N2 - Background: Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined. Methodology/Principal Findings: Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 μM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line. Conclusions/Significance: Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.

AB - Background: Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined. Methodology/Principal Findings: Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 μM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line. Conclusions/Significance: Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.

UR - http://www.scopus.com/inward/record.url?scp=84875147705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875147705&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0059012

DO - 10.1371/journal.pone.0059012

M3 - Article

C2 - 23527073

AN - SCOPUS:84875147705

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e59012

ER -