CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain | Cancer & Metabolism | Full Text

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain | Cancer & Metabolism | Full Text



Cancer & Metabolism

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

• Luke W. Thomas,
• Jenna M. Stephen,
• Cinzia Esposito,
• Simon Hoer,
• Robin Antrobus,
• Afshan Ahmed,
• Hasan Al-Habib and
• Margaret AshcroftEmail authorView ORCID ID profile

Cancer & Metabolism20197:2

https://doi.org/10.1186/s40170-019-0194-y

©  The Author(s). 2019

• Received: 2 January 2019
• Accepted: 5 February 2019
• Published: 6 March 2019

Abstract

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.

Keywords

• Coiled-coil-helix-coiled-coil-helix domain-containing 4 (CHCHD4)
• Hypoxia
• HIF-1α
• Mitochondria
• Respiratory chain
• Disulfide relay system
• Complex I
• Tumour growth
• Tumour metabolism