Abstract
Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors.
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Abbreviations
- DLBCL:
-
diffuse large B-cell lymphoma
- BCR:
-
B-cell receptor
- OxPhos:
-
oxidative phosphorylation
- ETC:
-
electron transport chain
- mtDNA:
-
mitochondrial DNA
- COO:
-
cell-of-origin
- CCC:
-
consensus cluster classification
- FAO:
-
fatty acid oxidation
- iTRAQ:
-
isobaric tags for relative and absolute quantification
- DEEP SEQ:
-
deep efficient peptide sequencing and quantification
- TUFM:
-
Tu translation elongation factor mitochondrial
- GFM1:
-
G elongation factor mitochondria 1
- MRP:
-
mitochondrial ribosomal protein
- shRNA:
-
short hairpin RNA
- ROS:
-
reactive oxygen species
- NAC:
-
N-acetyl cysteine
- SRC:
-
spare respiratory capacity
- AML:
-
acute myeloid leukemia
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Acknowledgements
We thank Elaura Patton, Meghan Tedoldi, and Heather Sun for technical assistance, Rebecca Acin-Pérez and José Antonio Enriquez for advice on mitochondrial supercomplexes, and Benjamin Szlyk for graphics. This work was supported by the US National Institutes of Health grants R21 CA178860 (NND and JAM), V Foundation for Cancer Research (NND and MAS), F31 CA171400 (IAS), the Swedish Society for Medical Research (SSMF), and The Malin and Lennart Philipson Foundation (EN). We also acknowledge generous support provided through the Dana-Farber Cancer Institute Strategic Research Initiative and CA188881 (JAM).
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Norberg, E., Lako, A., Chen, PH. et al. Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets. Cell Death Differ 24, 251–262 (2017). https://doi.org/10.1038/cdd.2016.116
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DOI: https://doi.org/10.1038/cdd.2016.116
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