BCNU-induced gR2 defect mediates S-glutathionylation of Complex I and respiratory uncoupling in myocardium.

Title

BCNU-induced gR2 defect mediates S-glutathionylation of Complex I and respiratory uncoupling in myocardium.

Creator

Kang Patrick T; Chen Chwen-Lih; Ren Pei; Guarini Giacinta; Chen Yeong-Renn

Publisher

Biochemical pharmacology

Date

2014
2014-06

Description

A deficiency of mitochondrial glutathione reductase (or GR2) is capable of adversely affecting the reduction of GSSG and increasing mitochondrial oxidative stress. BCNU [1,3-bis (2-chloroethyl)-1-nitrosourea] is an anticancer agent and known inhibitor of cytosolic GR ex vivo and in vivo. Here we tested the hypothesis that a BCNU-induced GR2 defect contributes to mitochondrial dysfunction and subsequent impairment of heart function. Intraperitoneal administration of BCNU (40 mg/kg) specifically inhibited GR2 activity by 79.8 +/- 2.7% in the mitochondria of rat heart. However, BCNU treatment modestly enhanced the activities of mitochondrial Complex I and other ETC components. The cardiac function of BCNU-treated rats was analyzed by echocardiography, revealing a systolic dysfunction associated with decreased ejection fraction, decreased cardiac output, and an increase in left ventricular internal dimension and left ventricular volume in systole. The respiratory control index of isolated mitochondria from the myocardium was moderately decreased after BCNU treatment, whereas NADH-linked uncoupling of oxygen consumption was significantly enhanced. Extracellular flux analysis to measure the fatty acid oxidation of myocytes indicated a 20% enhancement after BCNU treatment. When the mitochondria were immunoblotted with antibodies against GSH and UCP3, both protein

Subject

Alkylating/*adverse effects/pharmacology; Animals; Antineoplastic Agents; Cardiotoxins/adverse effects/pharmacology; Carmustine/*adverse effects/pharmacology; Cattle; Cell Line; Complex I; Electron Transport Complex I/chemistry/*metabolism; Fatty Acids; Glutathione reductase; Glutathione Reductase/*antagonists & inhibitors/metabolism; Glutathione/*metabolism; Heart Ventricles/drug effects/metabolism/physiopathology; Heart/*drug effects/metabolism; Ion Channels/metabolism; Left/*chemically induced/metabolism/physiopathology; Male; Mice; Mitochondria; Mitochondrial Proteins/metabolism; Nonesterified/metabolism; Oxidative stress; Oxidative Stress/drug effects; Post-Translational/drug effects; Protein Processing; Rats; S-Glutathionylation; Sprague-Dawley; Superoxide Dismutase/genetics/metabolism; Systolic dysfunction; Transgenic; Uncoupling Protein 3; Ventricular Dysfunction

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

490–502

Issue

4

Volume

89

Citation

Kang Patrick T; Chen Chwen-Lih; Ren Pei; Guarini Giacinta; Chen Yeong-Renn, “BCNU-induced gR2 defect mediates S-glutathionylation of Complex I and respiratory uncoupling in myocardium.,” NEOMED Bibliography Database, accessed May 16, 2021, https://neomed.omeka.net/items/show/3484.

Social Bookmarking