Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats - Relevance for mitochondrial dysfunction

Paulo J. Oliveira; Kendall B. Wallace

doi:10.1016/j.tox.2005.12.009

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats - Relevance for mitochondrial dysfunction

Paulo J. Oliveira, Kendall B. Wallace

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the molecule on the mitochondrial complex I generating in the process increased oxidative stress. Mitochondrial dysfunction, including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The adenine nucleotide translocator (ANT) has been suggested to be a principal component of the MPT pore and a possible target for DOX-induced cardiotoxicity. Nonetheless, no definitive evidence has been presented showing that altered ANT activity is due to decreased amount of the protein. By using carboxyatractyloside as a specific modulator of ANT activity and Western blotting, we observed that following DOX treatment in rats: (1) the amount of "functional ANT" that contributes to cardiac mitochondrial respiration with different substrates is reduced, (2) titrations with carboxyatracyloside revealed a lower threshold for MPT induction and most importantly, (3) a specific decrease in the amount of the ANT protein. This study identifies the ANT as one important target for DOX-induced cardiac toxicity and correlates the decrease in ANT protein concentration with inhibition of mitochondrial respiration and increased ability to form or at least regulate MPT pores.

Original language	English (US)
Pages (from-to)	160-168
Number of pages	9
Journal	Toxicology
Volume	220
Issue number	2-3
DOIs	https://doi.org/10.1016/j.tox.2005.12.009
State	Published - Mar 15 2006

Bibliographical note

Funding Information:
This work was supported by the NIH grant HL 58016. Paulo J. Oliveira is supported by a grant from the Portuguese Foundation for Science and Technology (SFRH/BPD/8359/2002). The expert assistance of Jamie Denninger and Jessica Berthiaume (Medical School, University of Minnesota-Duluth, USA) and Vilma A. Sardão (Center for Neurosciences and Cell Biology, University of Coimbra, Portugal) is greatly acknowledged.

Keywords

Adenine nucleotide translocator
Doxorubicin
Heart mitochondria

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1016/j.tox.2005.12.009

OpenUrl availability

Full text

Cite this

@article{8bcdba964de54a9e8053a11232bf15cf,

title = "Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats - Relevance for mitochondrial dysfunction",

abstract = "Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the molecule on the mitochondrial complex I generating in the process increased oxidative stress. Mitochondrial dysfunction, including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The adenine nucleotide translocator (ANT) has been suggested to be a principal component of the MPT pore and a possible target for DOX-induced cardiotoxicity. Nonetheless, no definitive evidence has been presented showing that altered ANT activity is due to decreased amount of the protein. By using carboxyatractyloside as a specific modulator of ANT activity and Western blotting, we observed that following DOX treatment in rats: (1) the amount of {"}functional ANT{"} that contributes to cardiac mitochondrial respiration with different substrates is reduced, (2) titrations with carboxyatracyloside revealed a lower threshold for MPT induction and most importantly, (3) a specific decrease in the amount of the ANT protein. This study identifies the ANT as one important target for DOX-induced cardiac toxicity and correlates the decrease in ANT protein concentration with inhibition of mitochondrial respiration and increased ability to form or at least regulate MPT pores.",

keywords = "Adenine nucleotide translocator, Doxorubicin, Heart mitochondria",

author = "Oliveira, {Paulo J.} and Wallace, {Kendall B.}",

note = "Funding Information: This work was supported by the NIH grant HL 58016. Paulo J. Oliveira is supported by a grant from the Portuguese Foundation for Science and Technology (SFRH/BPD/8359/2002). The expert assistance of Jamie Denninger and Jessica Berthiaume (Medical School, University of Minnesota-Duluth, USA) and Vilma A. Sard{\~a}o (Center for Neurosciences and Cell Biology, University of Coimbra, Portugal) is greatly acknowledged.",

year = "2006",

month = mar,

day = "15",

doi = "10.1016/j.tox.2005.12.009",

language = "English (US)",

volume = "220",

pages = "160--168",

journal = "Toxicology",

issn = "0300-483X",

publisher = "Elsevier Ireland Ltd",

number = "2-3",

}

TY - JOUR

T1 - Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats - Relevance for mitochondrial dysfunction

AU - Oliveira, Paulo J.

AU - Wallace, Kendall B.

N1 - Funding Information: This work was supported by the NIH grant HL 58016. Paulo J. Oliveira is supported by a grant from the Portuguese Foundation for Science and Technology (SFRH/BPD/8359/2002). The expert assistance of Jamie Denninger and Jessica Berthiaume (Medical School, University of Minnesota-Duluth, USA) and Vilma A. Sardão (Center for Neurosciences and Cell Biology, University of Coimbra, Portugal) is greatly acknowledged.

PY - 2006/3/15

Y1 - 2006/3/15

N2 - Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the molecule on the mitochondrial complex I generating in the process increased oxidative stress. Mitochondrial dysfunction, including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The adenine nucleotide translocator (ANT) has been suggested to be a principal component of the MPT pore and a possible target for DOX-induced cardiotoxicity. Nonetheless, no definitive evidence has been presented showing that altered ANT activity is due to decreased amount of the protein. By using carboxyatractyloside as a specific modulator of ANT activity and Western blotting, we observed that following DOX treatment in rats: (1) the amount of "functional ANT" that contributes to cardiac mitochondrial respiration with different substrates is reduced, (2) titrations with carboxyatracyloside revealed a lower threshold for MPT induction and most importantly, (3) a specific decrease in the amount of the ANT protein. This study identifies the ANT as one important target for DOX-induced cardiac toxicity and correlates the decrease in ANT protein concentration with inhibition of mitochondrial respiration and increased ability to form or at least regulate MPT pores.

AB - Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the molecule on the mitochondrial complex I generating in the process increased oxidative stress. Mitochondrial dysfunction, including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The adenine nucleotide translocator (ANT) has been suggested to be a principal component of the MPT pore and a possible target for DOX-induced cardiotoxicity. Nonetheless, no definitive evidence has been presented showing that altered ANT activity is due to decreased amount of the protein. By using carboxyatractyloside as a specific modulator of ANT activity and Western blotting, we observed that following DOX treatment in rats: (1) the amount of "functional ANT" that contributes to cardiac mitochondrial respiration with different substrates is reduced, (2) titrations with carboxyatracyloside revealed a lower threshold for MPT induction and most importantly, (3) a specific decrease in the amount of the ANT protein. This study identifies the ANT as one important target for DOX-induced cardiac toxicity and correlates the decrease in ANT protein concentration with inhibition of mitochondrial respiration and increased ability to form or at least regulate MPT pores.

KW - Adenine nucleotide translocator

KW - Doxorubicin

KW - Heart mitochondria

UR - http://www.scopus.com/inward/record.url?scp=33244492919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33244492919&partnerID=8YFLogxK

U2 - 10.1016/j.tox.2005.12.009

DO - 10.1016/j.tox.2005.12.009

M3 - Article

C2 - 16427179

AN - SCOPUS:33244492919

SN - 0300-483X

VL - 220

SP - 160

EP - 168

JO - Toxicology

JF - Toxicology

IS - 2-3

ER -

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats - Relevance for mitochondrial dysfunction

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this