PloS one, 2016-07, Vol.11 (7), p.e0158376
2016
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- Autor(en) / Beteiligte
- Titel
- Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes
- Ist Teil von
- PloS one, 2016-07, Vol.11 (7), p.e0158376
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0158376Titel-ID: cdi_plos_journals_1805488370
- Format
- –
- Schlagworte
- Animals, Antibiotics, Antineoplastic - pharmacology, Anticancer properties, Apoptosis, B cells, B-Lymphocytes - drug effects, B-Lymphocytes - metabolism, B-Lymphocytes - pathology, Barth Syndrome - metabolism, Barth Syndrome - pathology, Biochemistry, Bioenergetics, Biology and Life Sciences, Biosynthesis, Biotechnology, Carbonyls, Cardiolipin, Cardiolipins - metabolism, Cardiomyocytes, Caspase, Caspase 3 - genetics, Caspase 3 - metabolism, Caspase-3, Cell culture, Cell death, Cell Death - drug effects, Cell Line, Chemical synthesis, Control, Disease, Doxorubicin, Doxorubicin - pharmacology, Genetic disorders, Heart failure, Humans, Laboratories, Lipid peroxidation, Lipid Peroxidation - drug effects, Lymphocytes, Lymphocytes B, Medicine and Health Sciences, Metabolism, Metabolites, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Mutation, Myocytes, Cardiac - cytology, Myocytes, Cardiac - drug effects, Myocytes, Cardiac - metabolism, Oxidative stress, Oxidative Stress - drug effects, Oxygen, Peroxidation, Phospholipids, Physical Sciences, Primary Cell Culture, Protective Factors, Protein Carbonylation - drug effects, Proteins, Rats, Reactive oxygen species, Reactive Oxygen Species - metabolism, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, siRNA, Toxicity, Transcription Factors - antagonists & inhibitors, Transcription Factors - genetics, Transcription Factors - metabolism