Mitochondrial Metabolism as a Target for Cancer Therapy

Abstract

Recent evidence in humans and mice supports the notion that mitochondrial metabolism is active and necessary for tumor growth. Mitochondrial metabolism supports tumor anabolism by providing key metabolites for macromolecule synthesis and generating oncometabolites to maintain the cancer phenotype. Moreover, there are multiple clinical trials testing the efficacy of inhibiting mitochondrial metabolism as a new cancer therapeutic treatment. In this review, we discuss the rationale of using these anti-cancer agents in clinical trials and highlight how to effectively utilize them in different tumor contexts.

Keywords: metformin; mitochondria.

Figure 1.. Metabolism Supports Macromolecule Synthesis for Growth

Cancer cells upregulate both glycolysis and TCA cycle metabolism in order to provide the substrates required for synthesis of macromolecules such as lipids and nucleotides that are required for cell proliferation. Multiple substrates feed into these biosynthetic pathways, thus providing cancer cells with metabolic flexibility to support tumor growth.

Figure 2.. Mitochondrial ETC Serves Bioenergetic and Biosynthetic Needs of Cancer Cells

The five complexes of the ETC serve to produce the majority of ATP utilized by cancer cells as well as oxidize NADH and FADH2 to NAD+ and FAD, respectively. This allows for the TCA cycle to continue functioning, producing metabolites that support macromolecule synthesis. DHODH donates electrons to mitochondrial ubiquinone (CoQ) during the conversion of dihydroorotate to orotate, a key step in de novo pyrimidine synthesis. Atomic structures: mitochondrial complex I (PDB: 6RFR) (Parey et al., 2019), complex II (PDB: 1ZOY) (Sun et al., 2005), DHODH (PDB: 4LS1), complex III (PDB: 6Q9E) (Letts et al., 2019), cytochrome c (PDB: 2B4Z) (Mirkin et al., 2008), complex IV (PDB: 5Z62) (Zong et al., 2018), and ATP synthase (PDB: 5FL7) (Hahn et al., 2016).

Figure 3.. DHODH Links the Mitochondrial ETC to Pyrimidine Synthesis

DHODH, a mitochondrial enzyme tethered to the inner mitochondrial membrane, converts dihydroorotate to orotate in the intermembrane space. DHODH donates two electrons to mitochondrial ubiquinone (CoQ) within the ETC. There are currently FDA-approved DHODH inhibitors used for rheumatoid arthritis like leflunomide, as well as other newer DHODH inhibitors. DHODH inhibition has shown promise in preclinical studies of cancer. Atomic structures: DHODH (PDB: 4LS1), complex III (PDB: 6Q9E) (Letts et al., 2019), cytochrome c (PDB: 2B4Z) (Mirkin et al., 2008), and complex IV (PDB: 5Z62) (Zong et al., 2018).

Figure 4.. TCA Cycle Feeds Multiple Biosynthetic Pathways

Mitochondrial TCA cycle intermediates are utilized as precursors for biosynthetic purposes. This depletion of carbons requires replenishment, i.e., anaplerosis, usually from glutaminolysis and/or pyruvate carboxylase. Multiple inhibitors targeting different steps within the cycle have shown promise in phase I and II clinical trials.

Figure 5.. Rational Design of Metabolic Cancer Therapy

Combining Cancer genetics with metabolism-based imaging techniques will allow for patient stratification for targeted metabolic inhibitors. These metabolic inhibitors may be used in combination with chemotherapy, radiotherapy, or even immunotherapy to provide new avenues for cancer therapeutic strategies.