(i) Targeting ETC
Functional ETC supports OXPHOS activity and adenosine triphosphate (ATP) generation that is essential for tumorigenesis. Many ETC inhibitors, such as metformin, tamoxifen, α-tocopheryl succinate (α-TOS) and 3-bromopyruvate (3BP), act via disrupting the function of respiratory complexes of the ETC and inducing high levels of ROS to kill cancer cells [8, 9]. A novel approach of selective targeting of cancer mitochondria by tagging a cationic triphenylphosphonium (TPP+) group to anticancer compounds (e.g., α-TOS, tamoxifen and metformin) is considered as a mitochondrial-targeted therapy, delivering drugs preferentially into cancer cell mitochondria based on their higher transmembrane potential to trigger mitochondria-dependent apoptosis via rapid generation of ROS [9, 10]. Both MitoVES (mitochondrially targeted vitamin E succinate targeting complex II) and MitoTAM (mitochondrially targeted tamoxifen targeting complex I) have been prepared by tagging TPP+ to parental compounds efficiently kills colorectal, lung and breast cancer cells and inhibits tumor growth by interfering with complex I-/complex II-dependent respiration without systemic toxicity [11, 12].
(ii) Targeting glycolysis and OXPHOS
The glycolysis metabolic pathway directly affects mitochondrial function by providing key metabolic intermediates, such as pyruvate, for mitochondrial metabolism. Moreover, the ability of malignant cells to flexibly switching between glycolysis and oxidative phosphorylation appears to play a major role in multiple modes of resistance to oncogenic inhibition [1, 8]. Therefore, agents that target both glycolysis and OXPHOS function hold promise as an ideal anticancer therapeutic approach. Mitochondria-targeted therapeutics in combination with glycolytic inhibitors synergistically suppress tumor cell proliferation . Hexokinase II (HKII) is a major isoform of the enzyme overexpressed in cancer cells and plays an important role in maintaining glycolytic activity. It also binds to the voltage-dependent anion channel (VDAC) on the mitochondrial outer membrane. As such, inhibition of HKII will not only inhibit glycolysis but also suppresses the anti-apoptotic effects of the HKII–VDAC interaction. Several hexokinase inhibitors have been found to suppress cancer growth. FV-429 is a synthetic flavone with potent activity to induce apoptosis in cancer cells by inhibition of glycolysis via suppression of HKII and impairing mitochondrial function via interfering with the HKII–VDAC interaction, leading to activation of mitochondrial-mediated apoptosis. Metformin, a drug commonly used to treat diabetes, can suppress multiple types of cancers [13, 14]. Recent report showed that metformin inhibits HKII in lung carcinoma cells to decrease glucose uptake and phosphorylation. Combining metformin with 2-deoxyglucose (2-DG), a glycolysis inhibitor, depleted ATP in a synergistic manner and showed a strong synergy for the combined therapeutic effect in pancreatic cancer cells. The mitochondria-targeted drug, mitochondria-targeted carboxy-proxyl (Mito-CP) in combination with 2-DG led to significant tumor regression, suggesting that dual targeting of mitochondrial bioenergetic metabolism and glycolytic inhibitors may offer a promising chemotherapeutic strategy .
(iii) Targeting the TCA cycle
The TCA cycle is a source of electrons that feed into the ETC to drive the electrochemical proton gradient required for ATP generation. Isocitrate dehydrogenases 1 and 2 (IDH1, IDH2) catalyzes the conversion of isocitrate to α- ketoglutarate, playing a critical role in tumorigenesis . Mutations in IDH1 and IDH2 have been found in different human cancers  that render them as promising targets for anticancer therapy. Inhibitors of IDHs such as AGI-5198, AGI-6780, AG-120, AG-221, 3BP, and dichloroacetate possess high anticancer potential in a broad range of cancer types [8, 17].