PMID- 35478774
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220430
IS  - 2523-0204 (Electronic)
IS  - 2523-0204 (Linking)
VI  - 6
IP  - 4
DP  - 2022 Apr
TI  - COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide 
      species production in radioresistant GBM.
PG  - 45-60
LID - 10.15698/cst2022.04.266 [doi]
AB  - 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.
CI  - Copyright: (c) 2022 Oliva et al.
FAU - Oliva, Claudia R
AU  - Oliva CR
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA 52242.
FAU - Ali, Md Yousuf
AU  - Ali MY
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA 52242.
AD  - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, 
      Iowa City, IA 52242.
FAU - Flor, Susanne
AU  - Flor S
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA 52242.
FAU - Griguer, Corinne E
AU  - Griguer CE
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA 52242.
LA  - eng
PT  - Journal Article
DEP - 20220307
PL  - Austria
TA  - Cell Stress
JT  - Cell stress
JID - 101718867
PMC - PMC8988053
OTO - NOTNLM
OT  - COX4
OT  - GBM
OT  - cytochrome c oxidase
OT  - mitochondria
OT  - radioresistance
OT  - supercomplexes
OT  - superoxide
COIS- Conflict of Interest: The authors declare that no competing interests exist.
EDAT- 2022/04/29 06:00
MHDA- 2022/04/29 06:01
PMCR- 2022/03/07
CRDT- 2022/04/28 06:12
PHST- 2022/01/19 00:00 [received]
PHST- 2022/02/21 00:00 [revised]
PHST- 2022/02/28 00:00 [accepted]
PHST- 2022/04/28 06:12 [entrez]
PHST- 2022/04/29 06:00 [pubmed]
PHST- 2022/04/29 06:01 [medline]
PHST- 2022/03/07 00:00 [pmc-release]
AID - CST0272E105 [pii]
AID - 10.15698/cst2022.04.266 [doi]
PST - epublish
SO  - Cell Stress. 2022 Mar 7;6(4):45-60. doi: 10.15698/cst2022.04.266. eCollection 
      2022 Apr.