2. Academic Validation
  3. The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment

The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment

  • Cell Death Dis. 2023 Nov 30;14(11):784. doi: 10.1038/s41419-023-06275-0.
J Contenti 1 2,  Y Guo 3,  A Mazzu 3,  M Irondelle 3,  M Rouleau 4,  C Lago 5,  G Leva 5,  L Tiberi 5,  I Ben-Sahra 6,  F Bost 3,  N M Mazure 7
Affiliations

Affiliations

  • 1 Université Côte d'Azur, INSERM U1065, C3M, 151 Route de St Antoine de Ginestière, BP2 3194, CEDEX 03, 06204, Nice, France. contenti.j@chu-nice.fr.
  • 2 Pasteur II Hospital, Department of Emergency Medicine, University Hospital Center, 30 voie Romaine, 06000, Nice, France. contenti.j@chu-nice.fr.
  • 3 Université Côte d'Azur, INSERM U1065, C3M, 151 Route de St Antoine de Ginestière, BP2 3194, CEDEX 03, 06204, Nice, France.
  • 4 Université Côte d'Azur, Laboratoire de PhysioMédecine Moléculaire - LP2M, CNRS-UMR 7370, Faculty of Medicine, 28 ave de Valombrose, 06107, Nice Cedex 02, France.
  • 5 Armenise-Harvard Laboratory of Brain Disorders and Cancer, Department of Cellular, Computational and Integrative Biollogy - CIBIO, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
  • 6 Northwestern University Feinberg School of Medicine, Robert H. Lurie Cancer Center, 303 East Superior Street, Chicago, IL, 60611, USA.
  • 7 Université Côte d'Azur, INSERM U1065, C3M, 151 Route de St Antoine de Ginestière, BP2 3194, CEDEX 03, 06204, Nice, France. mazure@unice.fr.
PMID: 38036520 DOI: 10.1038/s41419-023-06275-0
Abstract

Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce Apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme Lactate Dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent Apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.

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