Journal article
COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM
Cell Stress, Vol.6(4), pp.45-60
03/07/2022
DOI: 10.15698/cst2022.04.266
PMCID: PMC8988053
PMID: 35478774
Abstract
Glioblastoma (GBM) is a fatal disease with recurrences often associated with radioresistance. Although often effective at treating newly diagnosed GBM, increasing evidence suggests that radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness. Using isogenic radiosensitive and radioresistant GBM cell lines and patient-derived xenolines, we found that acquired radioresistance is associated with a shift from a glycolytic metabolism to a more oxidative metabolism marked by a substantial increase in the activity of the mitochondrial respiratory chain complex cytochrome c oxidase (CcO). This elevated CcO activity was associated with a switch in the isoform expression of the CcO regulatory subunit COX4, from COX4-2 to COX4-1, assembly of CcO-containing mitochondrial supercomplexes (SCs), and reduced superoxide (O
2
•-
) production. Overexpression of COX4-1 in the radiosensitive cells was sufficient to promote the switch from glycolytic to oxidative metabolism and the incorporation of CcO into SCs, with a concomitant reduction in O
2
•-
production. Conversely, silencing of COX4-1 expression in normally radioresistant cells reduced CcO activity, promoted the disassembly of mitochondrial SCs, and increased O
2
•-
production. Additionally, gain or loss of COX4-1 expression was sufficient to induce the radioresistant or radiosensitive phenotype, respectively. Our results demonstrate that COX4-1 promotes SC assembly in GBM cells, and SC assembly may in turn regulate the production of reactive oxygen species and thus the acquisition of radioresistance in GBM.
Details
- Title: Subtitle
- COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM
- Creators
- Claudia R. Oliva - University of IowaMd Yousuf Ali - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242. Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242Susanne Flor - University of IowaCorinne E. Griguer - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Cell Stress, Vol.6(4), pp.45-60
- DOI
- 10.15698/cst2022.04.266
- PMID
- 35478774
- PMCID
- PMC8988053
- NLM abbreviation
- Cell Stress
- ISSN
- 2523-0204
- eISSN
- 2523-0204
- Publisher
- Shared Science Publishers OG
- Alternative title
- Mitochondrial Supercomplexes in Radioresistant GBM
- Language
- English
- Date published
- 03/07/2022
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984313073502771
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