Bioenergetic characterisation of malignant tissues revealed that different tumour
cells can catabolise multiple substrates as salvage pathways, in response to metabolic
stress. Altered metabolism in gliomas has received a lot of attention, especially
in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate
(2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas,
collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes
that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived
glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal
functions.Metabolic characteristics of human glioma cell models - including mitochondrial
function, glycolytic pathway and energy substrate oxidation - in relation to IDH mutation
status and after 2-HG incubation were studied to understand the Janus-faced role of
IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic
features were identified in glioma cells using wild-type and genetically engineered
IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression
studies and liquid chromatography-mass spectrometry.U251 glioma cells were characterised
by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase
(SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells
increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG
reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA
in SSADH expressing cells. SSADH protein overexpression was found in almost all studied
human cases with no significant association between SSADH expression and clinicopathological
parameters (e.g. IDH mutation).Our findings demonstrate that SSADH expression may
participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA
oxidation capacity may contribute to proliferation and worse prognosis of gliomas.
Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells.
Based on these data, GABA oxidation and SSADH activity could be additional therapeutic
targets in gliomas/glioblastomas.
