title: Mitochondrial control of apoptosis through modulation of cardiolipin oxidation in hepatocellular carcinoma: A novel link between oxidative stress and cancer.
abstract: Altered redox status in cancer cells has been linked to lipid peroxidation induced by reactive oxygen species (ROS) and subsequent formation of reactive lipid electrophiles, especially 4-hydroxy-nonenal (4-HNE). Emerging evidence suggests that cancer cells manipulate redox status to acquire anti-apoptotic phenotype but the underlying mechanisms are poorly understood. Cardiolipin (CL), a mitochondria-specific inner membrane phospholipid, is critical for maintaining mitochondrial function. Paradoxically, liver tissues contain tetralinoleoyl cardiolipin (TLCL) as the major CL in mitochondria yet emerging evidence suggests that ROS generated in mitochondria may lead to CL peroxidation and activation of intrinsic apoptosis. It remains unclear how CL oxidation leads to apoptosis and its relevance to the pathogenesis of hepatocellular carcinoma (HCC). We employed a mass spectrometry-based lipidomic approach to profile lipids in human tissues of HCC and found that CL was gradually decreased in tumor comparing to peripheral non-cancerous tissues, accompanied by a concomitant decrease of oxidized CL and its oxidation product, 4-HNE. Incubation of liver cancer cells with TLCL significantly restored apoptotic sensitivity accompanied by an increase of CL and its oxidation products when treated with staurosporine (STS) or Sorafenib (the standard treatment for late stage HCC patients). Our studies uncovered a novel mechanism by which cancer cells adopt to evade apoptosis, highlighting the importance of mitochondrial control of apoptosis through modulation of CL oxidation and subsequent 4-HNE formation in HCC. Thus manipulation of mitochondrial CL oxidation and lipid electrophile formation may have potential therapeutic value for diseases linked to oxidative stress and mitochondrial dysfunctions.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
authors.forename: Mengqing
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Division of Pathology, Clinical Hospital Centre & Medical Faculty, University of Zagreb, Croatia.
authors.forename: Kamelija
authors.initials: K
authors.lastname: Zarkovic
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
authors.forename: Rina
authors.initials: R
authors.lastname: Sa
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China.
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.affiliation: The Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Institute of Molecular Biosciences, Karl Franz University of Graz, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Waeg
authors.affiliation: Rudjer Boskovic Institute, Laboratory for Oxidative Stress, Zagreb, Croatia.
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS) Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: hyyin@sibs.ac.cn.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008055:Lipids / Q000737:chemistry / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D002308:Cardiolipins; D008055:Lipids; D017382:Reactive Oxygen Species; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxy-2-nonenal; Apoptosis; Cardiolipin; Hepatocellular carcinoma; Oxidative stress