COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM
Authors:Claudia R. Oliva1, Md Yousuf Ali1,2, Susanne Flor1 and Corinne E. Griguer1
1 Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242.
2 Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242.
Keywords:
supercomplexes, cytochrome c oxidase, radioresistance, GBM, superoxide, COX4, mitochondria.
Abbreviations:
AA – antimycin A,
CcO – cytochrome c oxidase,
FCCP – p-trifluoromethoxyphenylhydrazone,
GBM – glioblastoma,
IGA – in-gel activity,
MID – mean inactivation dose,
OCR – oxygen consumption rate,
OS – overall survival,
OXPHOS – oxidative phosphorylation,
SC – supercomplex,
ROS – reactive oxygen species.
Corresponding Author(s):
Conflict of interest statement:
The authors declare that no competing interests exist.
Please cite this article as:
Claudia R. Oliva, Md Yousuf Ali, Susanne Flor and Corinne E. Gri-guer (2022). COX4-1 promotes mitochondrial super-complex assembly and limits reactive oxide species production in radioresistant GBM. Cell Stress 6(4): 45-60. doi: 10.15698/cst2022.04.266
© 2022 Oliva et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
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 (O2●-) 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 O2●- production. Conversely, silencing of COX4-1 expression in normally radioresistant cells reduced CcO activity, promoted the disassembly of mitochondrial SCs, and increased O2●- 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.