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Tokarska-Schlattner 2007 Biochim Biophys Acta

From Bioblast
Publications in the MiPMap
Tokarska-Schlattner M, Dolder M, Gerber I, Speer O, Wallimann T, Schlattner U (2007) Reduced creatine-stimulated respiration in doxorubicin challenged mitochondria: Particular sensitivity of the heart. Biochim Biophys Acta 1767:1276-84.

ยป PMID: 17935690 Open Access

Tokarska-Schlattner M, Dolder M, Gerber I, Speer O, Wallimann T, Schlattner U (2007) Biochim Biophys Acta

Abstract: Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its use is limited by a risk of cardiotoxicity, which is not completely understood. Recently, we have shown that DXR impairs essential properties of purified mitochondrial creatine kinase (MtCK), with cardiac isoenzyme (sMtCK) being particularly sensitive. In this study we assessed the effects of DXR on respiration of isolated structurally and functionally intact heart mitochondria, containing sMtCK, in the presence and absence of externally added creatine (Cr), and compared these effects with the response of brain mitochondria expressing uMtCK, the ubiquitous, non-muscle MtCK isoenzyme. DXR impaired respiration of isolated heart mitochondria already after short-term exposure (minutes), affecting both ADP- and Cr-stimulated respiration. During a first short time span (minutes to 1 h), detachment of MtCK from membranes occurred, while a decrease of MtCK activity related to oxidative damage was only observed after longer exposure (several hours). The early inhibition of Cr-stimulated respiration, in addition to impairment of components of the respiratory chain involves a partial disturbance of functional coupling between MtCK and ANT, likely due to interaction of DXR with cardiolipin leading to competitive inhibition of MtCK/membrane binding. The relevance of these findings for the regulation of mitochondrial energy production in the heart, as well as the obvious differences of DXR action in the heart as compared to brain tissue, is discussed. โ€ข Keywords: Anthracycline, Creatine kinase, Cardiotoxicity, Isolated mitochondria, Creatine-simulated respiration

โ€ข O2k-Network Lab: CH Zurich Wallimann T, FR Grenoble Schlattner U

Labels: MiParea: Respiration, Comparative MiP;environmental MiP  Pathology: Other 

Organism: Human  Tissue;cell: Heart, Nervous system  Preparation: Isolated mitochondria, Enzyme 

Regulation: ADP, Inhibitor, PCr;Cr  Coupling state: OXPHOS 

HRR: Oxygraph-2k 

Pharmacology; Biotechnology