title: Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals.
abstract: Doxorubicin (Dox) 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 Dox-induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in Dox-induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in Dox-induced hepatic toxicity, which has not yet been investigated. Six-week-old male F344 rats were injected IP with 20 mg/kg of Dox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 h later. Dox decreased content of primary regulators of mitochondrial fusion (OPA1, MFN1, and MFN2) with no effect on regulators of fission (DRP1 and FIS1), 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 Dox-induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in Dox-induced hepatic injury.
authors.affiliation: Wingate University School of Pharmacy, Wingate, NC, 28174, USA.
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Dirks-Naylor
authors.forename: Samir A
authors.initials: SA
authors.lastname: Kouzi
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bero
authors.forename: Diep T
authors.initials: DT
authors.lastname: Phan
authors.forename: Heather N
authors.initials: HN
authors.lastname: Taylor
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Whitt
authors.forename: Raean
authors.initials: R
authors.lastname: Mabolo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D045304:Cytochromes c
keywords: caspase-9; glutathione; mitochondrial fission; mitophagy; proliferating cell nuclear antigen; protein carbonyls