Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

Laure Peyta (1) , Kathleen Jarnouen (2, 3) , Michelle Pinault (1) , Cédric Coulouarn (2, 3) , Cyrille Guimaraes (1) , Caroline Goupille (4, 1) , Jean-Paul Pais de Barros (5, 6) , Stephan Chevalier (1) , Jean-François Dumas (1) , François Maillot (1) , Grant M. Hatch (7) , Pascal Loyer (2, 3) , Stéphane Servais (1)

1 N2C - Nutrition, croissance et cancer (U 1069)
2 UR - Université de Rennes
3 Foie, métabolismes et cancer
4 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
5 LNC - Lipides - Nutrition - Cancer (U866)
6 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
7 University of Manitoba [Winnipeg]

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.

Keywords: Cardiolipin biosynthesis; Cytokines; Mitochondria; Energy wasting; Liver; Cardiolipin remodeling; Inflammation

Domains: Life Sciences [q-bio]; Humanities and Social Sciences; Library and information sciences

Laure Peyta, Kathleen Jarnouen, Michelle Pinault, Cédric Coulouarn, Cyrille Guimaraes, et al.. Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia. BBA - Biochimica et Biophysica Acta, 2015, 1851 (11), pp.1490-1500. ⟨10.1016/j.bbalip.2015.08.008⟩. ⟨hal-01197346⟩