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CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain
Luke W Thomas1, Jenna M Stephen1, Cinzia Esposito1,2
1Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AH UK.
Background:
Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is critical for regulating intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers correlates with increased tumour progression and poor patient survival.
Results:
Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS).
Conclusions:
Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology.
Insights
Coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) regulates tumor cell metabolism. Elevated CHCHD4 increases sensitivity to mitochondrial complex I inhibition, offering a potential cancer therapy target.
Area of Science:
- Cancer Biology
- Mitochondrial Metabolism
- Molecular Mechanisms
Background:
- Tumor cells utilize glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for survival.
- Mitochondrial OXPHOS is a therapeutic target in cancer, but its specific molecular mechanisms require further elucidation.
- Coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is crucial for intracellular oxygenation and the tumor cell response to hypoxia, with its overexpression linked to cancer progression.
Purpose of the Study:
- To investigate the role of CHCHD4 in regulating tumor cell proliferation and metabolism under varying oxygen conditions.
- To identify the molecular mechanisms by which CHCHD4 influences mitochondrial function and impacts tumor cell survival.
- To explore the therapeutic potential of targeting CHCHD4-mediated pathways in cancer treatment.
Main Methods:
- Stable isotope labeling with amino acids in cell culture (SILAC) was employed.
- Comprehensive analysis of the whole mitochondrial proteome was performed.
- The impact of CHCHD4 modulation on mitochondrial respiratory chain complex I (CI) activity and reactive oxygen species (ROS) production was assessed.
Main Results:
- Elevated CHCHD4 expression enhances tumor cell proliferation and metabolic advantage in both normoxia and hypoxia.
- CHCHD4 dynamically influences the expression of mitochondrial respiratory chain subunits, including essential complex I (CI) components.
- Loss of CHCHD4 confers resistance to CI inhibition, whereas its overexpression sensitizes tumor cells to CI inhibition, partly via mitochondrial ROS generation.
Conclusions:
- CHCHD4 plays a significant role in regulating tumor cell metabolism.
- CHCHD4 controls the mitochondrial respiratory chain and complex I (CI) biology, conferring metabolic vulnerabilities to tumor cells.
- Targeting CHCHD4-mediated pathways presents a promising strategy for cancer therapy by exploiting tumor cell metabolic weaknesses.
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