Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study

Claudia R. Oliva; Susanne Flor; Corinne E. Griguer

doi:10.3390/antiox15010040

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Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study

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Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study

Claudia R. Oliva, Susanne Flor and Corinne E. Griguer

Antioxidants, Vol.15(1), 40

12/28/2025

DOI: 10.3390/antiox15010040

PMID: 41596099

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Abstract

Ferroptosis is an iron-dependent, oxidative form of regulated cell death that has emerged as a therapeutic vulnerability in glioblastoma; however, the mitochondrial determinants that govern ferroptotic sensitivity remain poorly defined. Cytochrome c oxidase (CcO/Complex IV), a key regulator of mitochondrial respiration, contains two isoforms of subunit IV (COX4): COX4-1, a housekeeping isoform, and COX4-2, a stress-inducible variant. We previously found that COX4-1 expression protects glioma cells from erastin-induced ferroptosis, suggesting that mitochondria influence cell-death decisions independently of canonical ferroptotic regulators. Here, we used CRISPR-generated POLG-knockout ρ0 cells and transmitochondrial cybrids to isolate mitochondrial from nuclear contributions to ferroptosis sensitivity. Cybrids reconstituted with COX4-1-containing mitochondria restored CcO activity and recapitulated the ferroptosis-resistant phenotype, whereas COX4-2 cybrids remained insensitive to erastin. COX4-1 cybrids exhibited reduced labile iron, diminished cystine uptake, and low expression of SLC7A11 and GPX4, yet underwent apoptosis rather than ferroptosis upon erastin treatment. These findings demonstrate that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling away from ferroptosis toward apoptosis. Our results identify isoform-specific mitochondrial composition as a previously unrecognized determinant of regulated cell death and highlight COX4-1-driven mitochondrial remodeling as a potential mechanism of therapeutic resistance in glioblastoma.

ferroptosis

apoptosis

COX4-1 isoform

transmitochondrial cybrids

erastin

glioma

Details

Title: Subtitle: Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study
Creators: Claudia R. Oliva - University of Iowa
Susanne Flor - University of Iowa, Radiation Oncology
Corinne E. Griguer - University of Iowa
Resource Type: Journal article
Publication Details: Antioxidants, Vol.15(1), 40
DOI: 10.3390/antiox15010040
PMID: 41596099
NLM abbreviation: Antioxidants (Basel)
ISSN: 2076-3921
eISSN: 2076-3921
Publisher: MDPI
Grant note: National Institute of Neurological Disorders and Stroke: R01NS129702 National Cancer Institute: P30CA086862
This research was funded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award number R01NS129702. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA086862.
Language: English
Date published: 12/28/2025
Academic Unit: Radiation Oncology
Record Identifier: 9985116070602771

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