Peyta Laure, Jarnouen Kathleen, Pinault Michelle, Coulouarn Cedric, Guimaraes Cyrille, Goupille Caroline, de Barros Jean-Paul Pais, Chevalier Stephan, Dumas Jean-François, Maillot François, Hatch Grant M, Loyer Pascal, Servais Stephane
Inserm UMR1069, Nutrition, Croissance et Cancer, Université François Rabelais de Tours-10, bd Tonnellé, 37032 Tours Cedex, France.
Inserm UMR S-991, Foie, Métabolismes et Cancer, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes, France; Université de Rennes 1, 2 rue du Thabor CS46510, 35065 Rennes cedex, France.
Biochim Biophys Acta. 2015 Nov;1851(11):1490-500. doi: 10.1016/j.bbalip.2015.08.008. Epub 2015 Sep 13.
Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p<0.02) and cardiolipin synthase (CLS) activity decreased 44% (p<0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p<0.01) and 50% (p<0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p<0.05), mitochondrial oxygen consumption 33% (p<0.05), PGPS gene expression 44% (p<0.05) and MLCL AT-1 activity 20% (p<0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.
在肿瘤坏死因子α（TNFα）高表达的癌症恶病质大鼠模型中，心磷脂（CL）含量的积累导致肝脏线粒体能量消耗增加。在本研究中，我们调查了癌症恶病质中肝脏线粒体CL积累所涉及的机制，并研究了TNFα是否参与此过程并导致线粒体生物能量学改变。我们研究了癌症恶病质大鼠模型的肝脏线粒体以及暴露于20 ng/ml TNFα 12小时的HepaRG肝样细胞中，参与CL代谢的主要酶的基因、蛋白质表达和活性。与对照组相比，恶病质大鼠肝脏中磷脂酰甘油磷酸合酶（PGPS）基因表达增加了2.3倍（p<0.02），心磷脂合酶（CLS）活性降低了44%（p<0.03）。与对照组相比，恶病质大鼠肝脏中CL重塑酶单脂酰心磷脂酰基转移酶（MLCL AT-1）活性和塔法辛（TAZ）基因表达分别增加了30%（p<0.01）和50%（p<0.02）。与对照组相比，用TNFα孵育肝细胞可使CL含量增加15%（p<0.05），线粒体氧消耗增加33%（p<0.05），PGPS基因表达增加44%（p<0.05），MLCL AT-1活性增加20%（p<0.05）。上述发现强烈表明，在癌症恶病质中，TNFα通过上调PGPS表达增加CL含量，从而导致肝脏线粒体更高的能量消耗。
