Targeting mitochondria metabolism for cancer therapy

Abstract

Mitochondria have a well-recognized role in the production of ATP and the intermediates needed for macromolecule biosynthesis, such as nucleotides. Mitochondria also participate in the activation of signaling pathways. Overall, accumulating evidence now suggests that mitochondrial bioenergetics, biosynthesis and signaling are required for tumorigenesis. Thus, emerging studies have begun to demonstrate that mitochondrial metabolism is potentially a fruitful arena for cancer therapy. In this Perspective, we highlight recent developments in targeting mitochondrial metabolism for the treatment of cancer.

Figure 1. Mitochondria function as bioenergetic, biosynthetic and signaling organelles

Cancer cells catabolize pyruvate and glutamine through the TCA cycle, resulting in the generation of reducing equivalents such as NADH that donate electrons to the ETC. The ETC generates a proton gradient that is used for production of ATP, i.e., oxidative phosphorylation (blue). TCA cycle intermediates can also be directed into biosynthetic pathways (green) that allow for the production of macromolecules (lipids, amino acids and nucleotides). Finally, mitochondrial production of ROS and metabolites act as signaling molecules to alter protein function. Mitochondrial one-carbon metabolism produces NADPH to prevent accumulation of ROS in the mitochondrial matrix. NADPH maintains antioxidant activity of glutathione peroxidase (GPX) and thioredoxin reductases (TrxRs). TA, aminotransferase; VDAC, voltage-dependent anion channel. TRX, thioredoxin; GSH, glutathione; SOD2, superoxide dismutase 2, mitochondrial; 5,10-CH₂-THF, 5,10-methylene-tetrahydrofolate.

Figure 2. Targeting mitochondrial bioenergetic capacity

Mitochondrial ATP generation is necessary for tumorigenesis, and few molecules have demonstrated success in preclinical models of cancer. Specifically, (1) the biguanides metformin and phenformin inhibit mitochondrial complex I; (2) VLX600 inhibits the ETC at multiple sites; (3) tigecycline inhibits the mitochondrial ribosomal machinery and consequently the translation of ETC subunits; (4) gamitrinib is an inhibitor of mitochondrial chaperone proteins, such as TRAP-1 and HSP-90. Loss of these chaperones decreases ETC complex stability and subsequently reduces electron transport function. These therapies all share the same ultimate outcome with a decrease in mitochondrial ETC function to reduce mitochondrial bioenergetic capacity. mtDNA, mitochondrial DNA.

Figure 3. Targeting mitochondrial biosynthetic production

Mitochondrial TCA cycle intermediates are siphoned off for utilization as precursors for macromolecule production. Specifically, citrate is transported into the cytosol, where it is converted into acetyl-CoA (a precursor for fatty acid synthesis) and oxaloacetate. Thus, the TCA cycle intermediates have to be replenished for the cycle to continue functioning. Many cancer cells use glutamine, the most abundant amino acid in plasma, to replenish the TCA cycle. Glutaminase converts glutamine to glutamate, which is a precursor for glutathione synthesis. Next, glutamate is converted into the TCA cycle intermediate α-ketoglutarate by GLUD or aminotransferases (TA). The α-ketoglutarate generated from glutamine replenishes the TCA cycle and is also used as a substrate for dioxygenase-dependent reactions. Inhibition of GLS (1) or TA/GLUD (2) have shown efficacy in preclinical models of cancer. (3) Short-term inhibition of autophagy has also shown therapeutic efficacy in preclinical models of cancer. Autophagy generates metabolic substrates for mitochondrial metabolism, particularly glutamine.

Figure 4. Targeting mitochondrial redox signaling and balance

Mitochondrial ETC generates superoxide (O₂^•−) that can be converted into hydrogen peroxide (H₂O₂) by SOD2 or traverse through voltage-dependent anion channels (VDACs) into the cytosol. Subsequently, SOD1 converts superoxide into H₂O₂ to activate redox-dependent signaling. Mitochondrial ROS are necessary for cancer cell proliferation. Thus, mitochondrial-targeted antioxidants are effective in decreasing cancer cell proliferation. Mitochondria prevent accumulation of ROS to levels that would be detrimental to mitochondrial metabolism by increasing antioxidant capacity. NADPH is necessary to maintain the antioxidant function of glutathione peroxidase (GPXs) and thioredoxin reductase (TrxR). Mitochondria maintain redox balance by using SHMT2 and MTHFD2, enzymes in one-carbon metabolism, indicating that this pathway may be a therapeutic target.

Figure 5. Targeting mitochondrial metabolism

Small molecules conjugated to lipophilic cations such as tetraphenylphosphonium (TPP) result in their accumulation in the mitochondrial matrix. Lipophilic conjugated small molecules will first traverse across the plasma membrane and accumulate in the cytosol. This process is driven by the plasma membrane potential (Δψ_p). Subsequently, the mitochondrial membrane potential (Δψ_m) will drive the accumulation of these molecules into the mitochondria by several hundredfold.