Article
Mitochondrial 2-oxo-dehydrogenase complexes as a target for the therapy of glioblastomas
Mitochondriale 2-Oxo-Dehydrogenase-Komplexe als Target für die Therapie von Glioblastomen
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Authors
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Tim Seidenstücker
- Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie, Leipzig, Deutschland
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Jürgen Meixensberger
- Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie, Leipzig, Deutschland
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Frank Gaunitz
- Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie, Leipzig, Deutschland
| Published: | May 25, 2022 |
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Outline
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Objective: Glioblastoma (GBM) has a poor prognosis, and new therapeutic options are urgently needed. Here, we investigated, whether tumor-specific peculiarities with regard to subunits of mitochondrial 2 Oxo Dehydrogenase complexes (2-ODHCs) could be exploited for therapy.
Methods: Using data from the TCGA and the GTex project, we analyzed expression of the 11 known subunits of the four 2-ODHCs in GBM and normal tissue and their relation to overall (OS) and progression free survival (PFS). In addition, we performed RT-qPCR and Western Blots, analyzing mRNA and protein expression of the 11 subunits using 15 patient derived primary GBM and 5 fibroblast cell cultures. We also designed siRNAs inhibiting expression of subunits analyzing their effect on cell viability.
Results: In silico analysis of subunits of 2-ODHCs revealed overexpression of 9 subunits and a significant down-regulation of 1 subunit (p<0.05; OGDHL) in GBM (n=163) compared to normal brain tissue (n=207). Analyzing OS and PFS in patients with low (n=518) and high-grade gliomas (n=163) revealed highly significant Log rank (LR) values and hazard ratios (HR) for all subunits with the exception of DBT, BCKDHB and DLST. Among the most noticeable transcripts were that of genes encoding the E1 components DHTKD1 (LR= 0; HR= 0.26), OGDH (LR=0.01; HR1.4) and OGDHL (LR=0.004; HR=0.69). Cluster analysis of expression of all 11 subunits in primary GBM cultures identified two clusters, one with a generally higher expression of most components and one with a lower one. First experiments revealed that knockdown of OGDH in presence of pyruvate has a significant influence on ATP production and in presence of glutamine a significant influence on dehydrogenase activity in primary cell cultures (pyruvate: 88.2±4.9%; glutamine: 79.1±4.7%; both p<0.0005).
Conclusion: Compared to normal tissue, mitochondrial 2-ODHCs are upregulated in GBM and are at least required for ATP production in the presence of pyruvate or glutamine. Given significant differences in expression between GBM and normal tissue further analysis of these complexes and their contribution to tumor metabolism should be performed. Figure 1 [Fig. 1]
