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Mitochondrial matrix proteases as novel therapeutic targets in malignancy

Oncogene volume 33, pages 2690–2699 (2014)Cite this article

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Abstract

Although mitochondrial function is often altered in cancer, it remains essential for tumor viability. Tight control of protein homeostasis is required for the maintenance of mitochondrial function, and the mitochondrial matrix houses several coordinated protein quality control systems. These include three evolutionarily conserved proteases of the AAA+ superfamily—the Lon, ClpXP and m-AAA proteases. In humans, these proteases are proposed to degrade, process and chaperone the assembly of mitochondrial proteins in the matrix and inner membrane involved in oxidative phosphorylation, mitochondrial protein synthesis, mitochondrial network dynamics and nucleoid function. In addition, these proteases are upregulated by a variety of mitochondrial stressors, including oxidative stress, unfolded protein stress and imbalances in respiratory complex assembly. Given that tumor cells must survive and proliferate under dynamic cellular stress conditions, dysregulation of mitochondrial protein quality control systems may provide a selective advantage. The association of mitochondrial matrix AAA+ proteases with cancer and their potential for therapeutic modulation therefore warrant further consideration. Although our current knowledge of the endogenous human substrates of these proteases is limited, we highlight functional insights gained from cultured human cells, protease-deficient mouse models and other eukaryotic model organisms. We also review the consequences of disrupting mitochondrial matrix AAA+ proteases through genetic and pharmacological approaches, along with implications of these studies on the potential of these proteases as anticancer therapeutic targets.

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Acknowledgements

We thank members of the Schimmer lab for insightful discussions and apologize to colleagues whose work may not have been cited due to space constraints. ADS is a Leukemia and Lymphoma Society Scholar in Clinical Research.

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  1. Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    C A Goard & A D Schimmer

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Goard, C., Schimmer, A. Mitochondrial matrix proteases as novel therapeutic targets in malignancy. Oncogene 33, 2690–2699 (2014). https://doi.org/10.1038/onc.2013.228

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