Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy
Yueming Zhu, … , Douglas R. Spitz, David Gius
Yueming Zhu, … , Douglas R. Spitz, David Gius
Published August 31, 2018
Citation Information: J Clin Invest. 2018;128(9):3682-3691. https://doi.org/10.1172/JCI120844.
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Category: Review Series

Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy

Abstract

Mammalian cells use a complex network of redox-dependent processes necessary to maintain cellular integrity during oxidative metabolism, as well as to protect against and/or adapt to stress. The disruption of these redox-dependent processes, including those in the mitochondria, creates a cellular environment permissive for progression to a malignant phenotype and the development of resistance to commonly used anticancer agents. An extension of this paradigm is that when these mitochondrial functions are altered by the events leading to transformation and ensuing downstream metabolic processes, they can be used as molecular biomarkers or targets in the development of new therapeutic interventions to selectively kill and/or sensitize cancer versus normal cells. In this Review we propose that mitochondrial oxidative metabolism is altered in tumor cells, and the central theme of this dysregulation is electron transport chain activity, folate metabolism, NADH/NADPH metabolism, thiol-mediated detoxification pathways, and redox-active metal ion metabolism. It is proposed that specific subgroups of human malignancies display distinct mitochondrial transformative and/or tumor signatures that may benefit from agents that target these pathways.

Authors

Yueming Zhu, Angela Elizabeth Dean, Nobuo Horikoshi, Collin Heer, Douglas R. Spitz, David Gius

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Figure 1

The horse and cart model describes the relationship between mitochondrial metabolism, signal transduction, and gene expression in mammalian biology, as well as in degenerative diseases associated with aging and cancer.

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The horse and cart model describes the relationship between mitochondria...
(A) In healthy mammalian cells, the essential redox metabolic process occurring in the mitochondria and cytosol can be considered as the horse, and its related gene expression can be considered as the cart. In normal cells, oxidative metabolism and gene expression are tightly coupled via the nonequilibrium steady-state fluxes of reactive metabolic by-products and leaking electrons (e–) carriers, such as superoxide (O2•–) and hydrogen peroxide (H2O2). The level of DNA damage that occurs in a healthy cell is partially mitigated by ongoing DNA repair processes. (B) When the nonequilibrium steady state is disrupted, ROS and reactive oxidative by-products produced by oxidative metabolism (the horse) can increase oxidative damage in the genome, which will lead to the gradual deterioration of gene expression (the cart). Accumulation of DNA damage leads to cellular senescence or cancer. (C) The deregulated oxidative metabolism in cancer cells produces genomic instability that will eventually drag the cart off the cliff, so to speak, to the valley of death.