Stimulation of Oxidative phosphorylation
Mitochondrial bioenergetic modulation (basic science and drug discovery)
There is a need to discover drugs able to stimulate mitochondrial function to rescue the deficient bioenergetics in a large number of rare diseases. No drug able to activate or repair mitochondrial function is available in the clinics at the exception of bezafibrate, resveratrol or ibedenone, that showed a limited efficacy in a small number of patients. The project aims at the discovery of novel actionnable (druggable) targets involved in the regulation of mitochondrial function and quality control, and to develop, evaluate and patent new or repurposed drugs for bioenergetic therapy. A large viariety of experimental models ranging from cancer cells to human primary myoblasts or murine embryonic stem cells are used to investigate the molecular regulation of mitochondrial bioenergetics. We have also developped and funded a bioenergetic platform organized as a spin-out service company to offer services to the pharmaceutical industry and to perform innovative drug screening for the discovery of bioenergetically active candidates (www.cellomet.com). Lead compounds are then tested in rare diseases cell models in collaboration with MRGM’s clinical investigators. The MITOMODUL project also investigates mitochondrial drug toxicity.
Energy metabolism biochemical pathways also play a central role in the control of anabolism, gene expression and epigenetics. To decipher molecular actors involved in this interplay could reveal actionable molecular targets of interest for the development of innovative therapies.
Marija VLASKI (CR EFS)
Philippe BRUNET DE LA GRANGE (DR EFS)
Alice REFEYTON (PhD)
Project publications and patent
Targeting the mitochondrial trifunctional protein in oxidative lung carcinomas. [In revision].
EIF3F cooperates with STAT3 to regulate metastasis in human lung adenocarcinoma. [In revision].
3rd Prize (pitch). Meet2win_Oncology Business Convention [May 11th and 12th; Bordeaux]
PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metab. 2018 Sep 17.[Collaboration].
Redox mechanism of levobupivacaine cytostatic effect on human prostate cancer cells. Redox Biol. 2018 Sep. 18:33-42.
Energy Metabolism Rewiring Precedes UVB-Induced Primary Skin Tumor Formation. Cell Rep. 2018 Jun 19. 23(12):3621-3634 [Collaboration]
Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy. Biochim Biophys Acta Bioenerg. 2017 Aug. 1858(8):674-685. [Review]
High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy. FASEB J. 2017 Jan. 31(1):294-307. 14.
Enhanced OXPHOS, glutaminolysis and β-oxidation constitute the metastatic phenotype of melanoma cells. Biochem J. 2016 Mar 15. 473(6):703-15 [Collaboration]
Redox Homeostasis and Mitochondrial Dynamics. Cell Metab. 2015 Aug 4. 22(2):207-18. (Review)
EP17306858.6. Mitochondrial trifunctional protein (MTP) inhibitors for use in the treatment of high mitochondrial respiration (OX+) cancers.
H2020 ITN Marie Curie project TRANSMIT : Translating the role of mitochondria in tumorigenesis
Inca N° 2017-040. Priorité Tabac 2017