Amoedo 2021 J Clin Invest
|Amoedo ND, Sarlak S, Obre E, Esteves P, Bégueret H, Kieffer Y, Rousseau B, Dupis A, Izotte J, Bellance N, Dard L, Redonnet-Vernhet I, Punzi G, Rodrigues MF, Dumon E, Mafhouf W, Guyonnet-Dupérat V, Gales L, Palama T, Bellvert F, Dugot-Senan N, Claverol S, Baste JM, Lacombe D, Rezvani HR, Pierri CL, Mechta-Grigoriou F, Thumerel M, Rossignol R (2021) Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas. J Clin Invest 131:e133081.|
Amoedo Nivea Dias, Sarlak Saharnaz, Obre Emilie, Esteves Pauline, Begueret Hugues, Kieffer Yann, Rousseau Benoit, Dupis Alexis, Izotte Julien, Bellance Nadege, Dard Laetitia, Redonnet-Vernhet Isabelle, Punzi Giuseppe, Rodrigues Mariana Figueiredo, Elodie Dumon Elodie, Mafhouf Walid, Guyonnet-Duperat Veronique, Gales Lara, Palama Tony, Bellvert Floriant, Dugot-Senan Nathalie, Claverol Stephane, Baste Jean-Marc, Lacombe Didier, Rezvani Hamid Reza, Pierri Ciro Leonardo, Mechta-Grigoriou Fatima, Thumerel Matthie, Rossignol Rodrigue (2021) J Clin Invest
Abstract: Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer
Organism: Human Tissue;cell: Lung;gill Preparation: Intact cells
Coupling state: LEAK, ROUTINE Pathway: F, CIV HRR: Oxygraph-2k