Mitochondria Targeting as an Effective Strategy for Cancer Therapy

Abstract

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

Keywords: OXPHOS; heme; metabolism; mitochondria.

Figure 1

The metabolic steps of glycolysis and TCA cycle. Every step of glycolysis and the TCA cycle are shown. The NAD+/NADH and FAD/FADH2 generated or utilized are shown in red. The ATP/GTP synthesized and consumed is shown in pink. The numbers of ATP, GTP, NADH, and FADH2 generated when one molecule of glucose is consumed following glycolysis, and the TCA cycle are also shown.

Figure 2

Cancer cells exhibit altered metabolism that provides many potential targets for cancer therapy. Shown here are some altered metabolic processes that cancer cells rely on to satisfy their increased bioenergetic demands, including elevated glycolysis (reactions represented by green arrows), oxidative phosphorylation (reactions in TCA cycle and the electron transport chain represented with purple arrows), glutaminolysis (reaction represented by pink arrows), and elevated heme levels. These metabolic aberrations provide numerous targets for cancer therapy, which are represented using red five-pointed stars. In cancer cells, enzymes of the TCA cycle, such as aconitase (aconitate hydratase, AH), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and succinate dehydrogenase (SDH) are often mutated or deregulated. These mutated enzymes can be targeted for cancer therapy. Also shown is elevated glutamine transport and glutaminolysis (conversion of glutamine to glutamate by glutaminase or GLS) to support the excessive conversion of glucose to lactate that drives tumor cells to use anaplerotic reactions to replenish TCA cycle intermediates. The inhibition of glutaminolysis may prove to be an effective therapeutic strategy for the treatment of cancer. Heme synthesis involving the enzyme ALAS1 (aminolevulinate synthase), the rate-limiting step of heme biosynthesis, is elevated in NSCLC cells (reactions represented with brown dotted arrows). Also elevated is the process of heme uptake by heme transport proteins, HCP1 (Heme carrier protein 1) and HRG1 (Heme responsive gene 1), represented here as the brown cylinder. Both processes contribute to elevated levels of heme in NSCLC cells. Elevated heme via increased heme synthesis and/or uptake is exhibited by cancer cells to fuel elevated OXPHOS in NSCLC. Limiting heme availability by inhibiting heme synthesis or uptake can also be a novel and effective therapeutic strategy that targets OXPHOS in NSCLC. Also shown is the electron transport chain, including complexes I, II, III, IV, V, and coenzyme Q or ubiquinone (shuttles electrons between complexes I or II, and complex III). Proper functioning of the ETC is required for energy generation via OXPHOS. These ETC complex proteins can also be targeted for cancer therapy.