Correction: Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations. Citation: Pereira GC, Pereira SP, Pereira CV, Lumini JA, Magalhães J, et al. (2012) Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific. PLoS ONE 7(6): e38867. doi:10.1371/journal.pone.0038867 Editor: Valdur Saks, Université Joseph Fourier, France Received March 2, 2012; Accepted May 13, 2012; Published June 22, 2012 Copyright: 2012 Pereira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The present work was funded by the Foundation for Science and Technology (FCT), Portugal: research grants PTDC/SAU-OSM/64084/2006 and PTDC/ SAU-OSM/104731/2008 (PJO), through FEDER/COMPETE/National funds; Post-Doc fellowships SFRH/BPD/42525/2007 to AA and SFRH/BPD/66935/2009 to JM; and, Ph.D. fellowships SFRH/BD/30906/2006 to JAL, SFRH/BD/36938/2007 to GCP, SFRH/BD/48029/2008 to CVP, SFRH/BD/64247/2009 to SPP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]