Comparative survey of mitochondrial ultrastructure in IDH1-mutant astrocytoma and IDH1-wildtype glioblastoma (GBM)

ABSTRACT

Gliomas are the most common malignant brain tumors with poor prognosis. The WHO’s classification recognizes isocitrate dehydrogenase 1 (IDH1) mutant astrocytoma and IDH1-wildtype glioblastoma (GBM). The IDH1 mutation confers a survival advantage over the wildtype. There are several explanations for the metabolic advantage of the IDH1 mutation, some involve mitochondrial implications. Since an ultrastructural comparison of both tumor genotypes is still lacking, we surveyed the ultrastructural effects of the IDH1 mutation on the mitochondria of the IDH1-mutant astrocytoma (n = 15) and IDH1-wildtype glioblastoma (n = 15) tumors. Our results show that both IDH1 genotypes have degenerate and uncoupled mitochondria; this has not been reported before. The presence of ample lipid inclusions and lipid droplets in the cytoplasm of both genotypes support our conclusion of dysfunctional uncoupled mitochondria. Thus, the IDH1 mutation may have no ultrastructural consequences on the mitochondria, and the aberrant mitochondria in both genotypes may be the result of other unknown mutations. The status of the mitochondria in these genotypes portends a clinical challenge since tumor cells with uncoupled mitochondria are more primitive, aggressive, and considerably treatment resistant.

KEYWORDS:

• Glioblastoma
• mitochondria
• isocitrate dehydrogenase
• TCA cycle
• beta-oxidation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Abbreviations

Glioblastoma = GBM; isocitrate dehydrogenase = IDH; IDH-mutant = IDH-mt; IDH-wildtype = IDH-wt, tricarboxylic acid cycle (TCA), alpha-ketoglutarate = AKG.

Authorship

Conception and design of the study/experiments: MAA, OA

Experimental implementation/Data acquisition: MAA

Data analysis and interpretation: HM, MAA, OA

Drafting of manuscript: HM, MAA, HSL, OA

Revision of the manuscript and approval of final version: HM, MAA, HSL, OA

All listed authors participated the writing of the manuscript and have read and approved the final version.

Additional information

Funding

Dr. Aboud is supported in part by The UC Davis Paul Calabresi Career Development Award for Clinical Oncology as funded by the National Cancer Institute, National Institutes of Health through grant #2K12CA138464-11.