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Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals
Author(s) -
DirksNaylor Amie J.,
Kouzi Samir A.,
Bero Joseph D.,
Phan Diep T.,
Taylor Heather N.,
Whitt Stephanie D.,
Mabolo Raean
Publication year - 2014
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12073
Subject(s) - mitophagy , toxicity , mitochondrial fission , mitochondrion , oxidative stress , mitochondrial toxicity , pharmacology , biology , apoptosis , microbiology and biotechnology , biochemistry , medicine , autophagy
Doxorubicin ( D ox) is an effective chemotherapeutic agent, but known to cause cardiac and hepatic toxicity. Mechanisms of toxicity have not been clearly identified, but shown to involve oxidative stress and mitochondrial dysfunction. However, antioxidant supplementation has only shown modest protection from D ox‐induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in D ox‐induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in D ox‐induced hepatic toxicity, which has not yet been investigated. Six‐week‐old male F 344 rats were injected IP with 20 mg/kg of D ox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 h later. D ox decreased content of primary regulators of mitochondrial fusion ( OPA 1, MFN 1, and MFN 2) with no effect on regulators of fission ( DRP 1 and FIS 1), thus shifting the balance favoring mitochondrial fission. Moreover, it was determined that mitochondrial fission was likely not coupled to cell proliferation or cytochrome c release leading to the activation of mitochondrial‐mediated apoptotic signaling. Rather, mitochondrial fission may be coupled to mitophagy and may be an adaptive response to protect against D ox‐induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in D ox‐induced hepatic injury.