TY - JOUR
AU - Yoo, So, Young
AB - Abstract Mitochondria play pivotal roles in most eukaryotic cells, ranging from energy production to regulation of apoptosis. As sites of cellular respiration, mitochondria experience accumulation of reactive oxygen species (ROS) due to damage in electron transport chain carriers. Mutations in mitochondrial DNA (mtDNA) as well as nuclear DNA are reported in various cancers. Mitochondria have a dual role in cancer: the development of tumors due to mutations in mitochondrial genome and the generation of ROS. Impairment in the mitochondria-regulated apoptosis pathway accelerates tumorigenesis. Numerous strategies targeting mitochondria have been developed to induce the mitochondrial (i.e. intrinsic) apoptosis pathway in cancer cells. This review elaborates the roles of mitochondria in cancer with respect to mutations and apoptosis and discusses mitochondria-targeting strategies as cancer therapies to enhance the killing of cancer cells. Introduction Cancer, the uncontrolled proliferation of cells, is induced by impairments in the cell cycle (1). The hallmarks of cancer cells are overexpression of oncogenes and/or downregulation of tumor suppressor genes (2). Normally, cell proliferation is controlled by several signaling mechanisms. For instance, damage in cell structures and molecules summons the programmed cell death process called apoptosis (3). In cancer cells, however, this mechanism is malfunctional, resulting in uncontrolled division of cells to form tumors (4). Cancer therapy involves various strategies to target and kill tumor cells. Chemotherapy and radiotherapy are the main remedies in this category (5), but limitations such as drug resistance in chemotherapy significantly affect the treatment outcomes (6). Modern approaches such as oncolytic virotherapy and nanoparticle-based therapies therefore play evolutionary roles in the current scenario (7–9). Additionally, a new approach that targets the cellular processes that induce apoptosis of cancer cells is now being considered (10). Since tumor cells lack apoptotic mechanisms during the early stages, targeting mitochondria-related mechanisms can be a good strategy (11). Mitochondria are subcellular, double-membrane organelles. It is hypothesized that about 2 million years ago, the engulfment of an α-proteobacterium by a precursor of the modern eukaryotic cell gave rise to the mitochondrion (12). This endosymbiotic origin of mitochondria is supported by their protein content (13). In addition, analysis of mitochondria by modern approaches, such as proteomics, genomics and bioinformatics, supports this theory. Mitochondrial proteins vary from species to species in response to cellular- and tissue-specific functions (14,15). Internal to the mitochondria is the inner membrane consisting of electron transport carrier proteins (16). The inner part is called the matrix and is the site for tricarboxylic acid (TCA) cycle and β-oxidation of fatty acids. The inner membrane is surrounded by a selectively permeable outer membrane (17). Thus, the powerhouse of eukaryotic cells, mitochondria are the site of oxidative phosphorylation (OXPHOS), the final step of cellular respiration, and are also involved in the apoptosis pathway (Figure 1) (18). Figure 1. View largeDownload slide Bioenergetics and apoptotic roles of mitochondria in normal cells. Mitochondria generate ATP via the ETC complexes in a process called oxidative phosphorylation. In apoptosis, Adenine nucleotide translocator (ANT) and VDAC form a complex and induce apoptosis (intrinsic pathway). Cytochrome c is released from the intermembrane space and activates Apaf-1. Procaspases, also present in the intermembrane space, are activated by Apaf-1. Figure 1. View largeDownload slide Bioenergetics and apoptotic roles of mitochondria in normal cells. Mitochondria generate ATP via the ETC complexes in a process called oxidative phosphorylation. In apoptosis, Adenine nucleotide translocator (ANT) and VDAC form a complex and induce apoptosis (intrinsic pathway). Cytochrome c is released from the intermembrane space and activates Apaf-1. Procaspases, also present in the intermembrane space, are activated by Apaf-1. Mitochondria have their own double-stranded circular mitochondrial DNA (mtDNA) genome (Supplementary Figure S1, available at Carcinogenesis Online). The human mitochondrial genome is 16.6 kb in size and encodes 37 genes, among which 13 encode polypeptides involved in OXPHOS, 2 encode rRNAs and the remaining 22 genes encode tRNAs (19). The other genes involved in mitochondrial metabolism are encoded by nuclear DNA (nDNA). The total number of mitochondria varies from cell to cell, depending on their nature. For instance, hepatocytes have several hundred mitochondria. Likewise, numerous copies of mtDNA are present in a single mitochondrion; therefore, there might be some mutated mtDNAs in the organelle. These conditions contribute to the homoplasmic (identical copies of mtDNAs in a mitochondrion) and heteroplasmic (mutated and normal copies of mtDNA in a mitochondrion) nature of mitochondrial populations (20,21). Besides this, single nucleotide polymorphism-based mtDNA haplogroups also vary among the human populations, and maximum haplogroups have been found in numerous cancers (22–24). Contrary to the nDNA, the mtDNA has a high probability of undergoing mutations due to their exposure to reactive oxygen species (ROS) and absence of histones in the mitochondrial genome (25). As mitochondria are associated with energy metabolism, mutations in mtDNA can cause several diseases, most of which are associated with neuromuscular disabilities. For instance, the mutation 3460G>A in the ND1 gene causes Leber hereditary optic neuropathy. Single, large-scaled deletions in several genes are reported in Kearns–Sayre syndrome, chronic progressive external ophthalmoplegia and Pearson syndrome disorders. In addition, mutations (3243A>G and 3271T>C) in the TRNL1 gene lead to myopathy, encephalopathy lactic acidosis and stroke-like episodes (MELAS). The common clinical phenotypes of these disorders are progressive myopathy, ophthalmoplegia, cardiomyopathy and lactic acidosis. Dysfunctions in mitochondrial metabolism, such as in TCA cycle and electron transport, are also associated with cancer (26). Defective mitochondria in cancer cells may favor tumorigenesis through a dysfunctional metabolism and impaired apoptosis. This review discusses the mitochondrial changes in cancer cells with respect to mutations in the mtDNA, metabolism and apoptosis. Finally, mitochondria-targeting strategies in cancer therapy will also be deliberated. The role of mitochondria in tumorigenesis Mitochondrial metabolism differs from that of their normal counterparts in cancer cells. Aerobic glycolysis, ROS accumulation, antiapoptotic signals and hypoxia are major characteristics of mitochondria in cancer cells. As mentioned previously, deregulation of enzymes caused by mutations in mtDNA as well as in nDNA leads to the accumulation of intermediary metabolites in cancer cells. These features are closely interlinked, thereby accelerating tumorigenesis (Figure 2). Figure 2. View largeDownload slide Major mitochondrial characteristics of cancer cells. Accumulation of TCA metabolites due to nDNA mutations, activation of the NRF2 pathway, ROS-induced cancer cell proliferation through HIF1α and FUS-JUN and aerobic glycolysis (Warburg effect) are important characteristics of cancer cells. In addition, the metabolism of ROS production, activation of oncogenes, mitochondrial membrane potential (ψ∆m) and cytosolic Ca2+ concentrations are also influenced by cancer cell mitochondria. Figure 2. View largeDownload slide Major mitochondrial characteristics of cancer cells. Accumulation of TCA metabolites due to nDNA mutations, activation of the NRF2 pathway, ROS-induced cancer cell proliferation through HIF1α and FUS-JUN and aerobic glycolysis (Warburg effect) are important characteristics of cancer cells. In addition, the metabolism of ROS production, activation of oncogenes, mitochondrial membrane potential (ψ∆m) and cytosolic Ca2+ concentrations are also influenced by cancer cell mitochondria. Oxidative phosphorylation and generation of ROS OXPHOS generates adenosine triphosphate (ATP) via the electron transport chain (ETC), which consists of a series of complexes (I to IV) in the inner membrane of mitochondria wherein electrons are transferred. The continuous flow of H+ from the matrix creates a high electrochemical potential across the inner mitochondrial membrane. Leakage of ETC contributes to the formation of ROS, namely, superoxide, free hydroxyl radicals and hydrogen peroxide (H2O2). Mitochondria have multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin and peroxiredoxins (27). Normal cells maintain a constant balance between the ROS and antioxidant pathways. In contrast, cancer cells generate more ROS. A high level of ROS induces the oxidation of macromolecules, such as proteins, lipids and DNA (Figure 3). Leakage in the inner membrane generates ROS and affects the mtDNA located in the matrix. Cytoplasmic hybrid (cybrid) technology has been employed to elucidate the roles of mtDNA mutations and ROS generation in cancer development. Interchanging endogenous mtDNA of mouse tumor cell lines (from P29 to A11 and vice versa) has clearly indicated that G13997A and 13885insC mutations in the gene encoding NADH dehydrogenase subunit 6 of complex I play a role in cancer metastasis (28). Figure 3. View largeDownload slide Mitochondria in cancer cells: tumorigenic aspects and targeting for cancer therapy. In the figure, the left side of the mitochondrion depicts roles of mitochondria in tumorigenesis. Production of ROS causes mutations in mtDNA and nDNA, protein oxidation and lipid peroxidation. These damaged macromolecules alter the mitochondrial metabolism, for example by accumulation of the TCA cycle metabolites that lead to HIF1α activation. ROS also induce oxidative signaling and activates p53, AP1, NRF2 and NF-κB. The right side represents strategies for targeting therapy: inducing apoptosis by nanomaterials, inhibition of mitochondrial ribosomal protein synthesis by antibiotics, preventing HSP90 interaction and targeting OMM by nanomaterials. Figure 3. View largeDownload slide Mitochondria in cancer cells: tumorigenic aspects and targeting for cancer therapy. In the figure, the left side of the mitochondrion depicts roles of mitochondria in tumorigenesis. Production of ROS causes mutations in mtDNA and nDNA, protein oxidation and lipid peroxidation. These damaged macromolecules alter the mitochondrial metabolism, for example by accumulation of the TCA cycle metabolites that lead to HIF1α activation. ROS also induce oxidative signaling and activates p53, AP1, NRF2 and NF-κB. The right side represents strategies for targeting therapy: inducing apoptosis by nanomaterials, inhibition of mitochondrial ribosomal protein synthesis by antibiotics, preventing HSP90 interaction and targeting OMM by nanomaterials. Generation of ROS also influences cell signaling. H2O2 oxidizes reactive cysteine groups in proteins, leading to protein thiol oxidation. Such conformational and functional changes are reported in the catalytic site of lipid and protein phosphatases (29). In addition, ROS-related mtDNA instability increases tumor numbers and growth in the small intestine of adenomatous polyposis coli/multiple intestinal neoplasia (APCMin/+) mice (30). TCA cycle Accumulated intermediate metabolites of the TCA cycle play critical roles in tumorigenesis. Due to the amphoteric nature of the TCA cycle, these products are used for the synthesis of fatty acids and amino acids. Interestingly, mitochondria defective in the TCA cycle enzymes also provide energy for lipid synthesis in cancer cells via the reductive carboxylation of glutamine (31). Mutations in TCA cycle enzyme-encoding genes play major roles in the activation of hypoxia-inducible factors (HIFs). These are summarized in Table 1. Table 1. Mutations in TCA cycle enzyme-encoding genes Enzyme Gene Mutation and phenotypic effect Cancer type Reference SDH SDHA SDHB SDHC SDHD SDHAF2 Homozygous null mutations: SDH inhibition causes elevated succinate levels in cytosol and mitochondria. As a result, inhibition of PHDs creates stabilization of HIF1α. Paragangliomas and pheochromocytomas (117–121) FH FH Homozygous null mutations: accumulation of fumarate and decreased malate and citrate levels. Stabilization of HIF1α. Multiple cutaneous, uterine leiomyomata and advanced kidney cancer (122,123) IDH1 IDH1 IDH2 Heterozygous missense mutations: IDH1-R132, IDH2-R140 and IDH2-R172. Mutated enzymes use NADPH to reduce α-ketoglutarate to R-2HG. Glioblastomas (124–126) Enzyme Gene Mutation and phenotypic effect Cancer type Reference SDH SDHA SDHB SDHC SDHD SDHAF2 Homozygous null mutations: SDH inhibition causes elevated succinate levels in cytosol and mitochondria. As a result, inhibition of PHDs creates stabilization of HIF1α. Paragangliomas and pheochromocytomas (117–121) FH FH Homozygous null mutations: accumulation of fumarate and decreased malate and citrate levels. Stabilization of HIF1α. Multiple cutaneous, uterine leiomyomata and advanced kidney cancer (122,123) IDH1 IDH1 IDH2 Heterozygous missense mutations: IDH1-R132, IDH2-R140 and IDH2-R172. Mutated enzymes use NADPH to reduce α-ketoglutarate to R-2HG. Glioblastomas (124–126) FH, fumarate hydratase; HIF1α, hypoxia-inducible factor 1α; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; R-2HG, (R)-2‑hydroxyglutarate; SDHA, succinate dehydrogenase A; SDHB, succinate dehydrogenase B; SDHC, succinate dehydrogenase C; SDHD, succinate dehydrogenase D; SDHAF2, succinate dehydrogenase assembling factor 2. View Large Table 1. Mutations in TCA cycle enzyme-encoding genes Enzyme Gene Mutation and phenotypic effect Cancer type Reference SDH SDHA SDHB SDHC SDHD SDHAF2 Homozygous null mutations: SDH inhibition causes elevated succinate levels in cytosol and mitochondria. As a result, inhibition of PHDs creates stabilization of HIF1α. Paragangliomas and pheochromocytomas (117–121) FH FH Homozygous null mutations: accumulation of fumarate and decreased malate and citrate levels. Stabilization of HIF1α. Multiple cutaneous, uterine leiomyomata and advanced kidney cancer (122,123) IDH1 IDH1 IDH2 Heterozygous missense mutations: IDH1-R132, IDH2-R140 and IDH2-R172. Mutated enzymes use NADPH to reduce α-ketoglutarate to R-2HG. Glioblastomas (124–126) Enzyme Gene Mutation and phenotypic effect Cancer type Reference SDH SDHA SDHB SDHC SDHD SDHAF2 Homozygous null mutations: SDH inhibition causes elevated succinate levels in cytosol and mitochondria. As a result, inhibition of PHDs creates stabilization of HIF1α. Paragangliomas and pheochromocytomas (117–121) FH FH Homozygous null mutations: accumulation of fumarate and decreased malate and citrate levels. Stabilization of HIF1α. Multiple cutaneous, uterine leiomyomata and advanced kidney cancer (122,123) IDH1 IDH1 IDH2 Heterozygous missense mutations: IDH1-R132, IDH2-R140 and IDH2-R172. Mutated enzymes use NADPH to reduce α-ketoglutarate to R-2HG. Glioblastomas (124–126) FH, fumarate hydratase; HIF1α, hypoxia-inducible factor 1α; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; R-2HG, (R)-2‑hydroxyglutarate; SDHA, succinate dehydrogenase A; SDHB, succinate dehydrogenase B; SDHC, succinate dehydrogenase C; SDHD, succinate dehydrogenase D; SDHAF2, succinate dehydrogenase assembling factor 2. View Large Hypoxia The low level of oxygen (O2) contributes to a hypoxic environment in cells. Hypoxia induces the production of ROS by ETC, and the release of ROS to the cytosol activates oxidative stress and related signaling. It also activates HIFs and proliferation of tumor cells. HIF stabilization is tightly regulated by prolyl hydroxylases (PHDs) in a 2-oxoglutarate- and O2-dependent reaction; PHDs hydroxylate the conserved proline residues in the α subunits of HIF1 and HIF2 located within an O2-dependent degradation domain (32,33). Mitochondria-derived ROS stabilize the HIF1 and HIF2 through inhibition of PHDs (34). Furthermore, ROS accumulation in cytosol stimulates oxidative signaling and transcription factors (p53, AP1, NRF2 and NF-κB) that are closely associated with tumorigenesis-related gene expression (26). Akt accumulates in the mitochondria during hypoxia. Phosphoproteomic screening has revealed the phosphorylation of pyruvate dehydrogenase kinase 1 on Thr346 in prostate adenocarcinoma PC3 cells. In tumor cells, inactivation of the pyruvate dehydrogenase complex leads to metabolic reprogramming toward glycolysis, thereby preventing apoptosis and autophagy and allowing tumor cell proliferation in the presence of severe hypoxia (35). Accumulation of TCA cycle metabolites also contributes to generation of hypoxia, as described in the previous section. Apoptosis Mitochondria also regulate cell senescence through cytochrome c. The B-cell lymphoma 2 (Bcl-2) family of proteins tightly regulate apoptosis in cells (36). Disruption of the apoptotic process leads to clonal outgrowth of mutated cell populations, resulting in the development of cancer (37). Overexpression of antiapoptotic proteins, such as Bcl-XL and Bcl-2, has been associated with tumor initiation, progression and resistance to therapy (38). Cytochrome c released during mitochondrial outer membrane permeabilization (MOMP) is degraded by an E3 ligase (Parkin-like cytoplasmic protein, PARC/CUL9) in neurons and brain tumor cells, resulting in the prolonged survival of cancer cells (39). Additionally, the oncogenic potential of apoptotic mechanisms is proved by ‘minority MOMP’ that yields limited caspase activation which results in DNA damage, genomic instability, cellular transformation and tumorigenesis (40). Survivin is a mitochondrial protein overexpressed in cancer cells and is rapidly discharged to the cytosol in response to cell death stimulation, where it halts caspase activation and inhibits apoptosis (41). The interaction between heat shock protein 60 (HSP60) and survivin inhibits the apoptosis. Removal of HSP60 by small interfering RNA destabilizes the survivin pool in the mitochondria and induces mitochondrial dysfunction with activation of caspase-dependent apoptosis. This response disrupts Hsp60-p53 complex, thereby further resulting in p53 stabilization. Reports have indicated the upregulation of pro-apoptotic Bax and Bax-dependent apoptosis under these conditions (42). Other mitochondrial molecular chaperons such as HSP90 and its related molecule, TNF receptor-associated protein 1 (TRAP-1), also inhibit apoptosis. HSP90/TRAP-1 complex interacts with cyclophilin D (an immunophilin that favors mitochondrial cell death) and antagonizes the cell death. Disassembly of this network accelerates apoptosis in tumor cells (43). Overall, mitochondrial HSPs usually favor tumor cell survival by inhibiting apoptosis through protein folding/refolding mechanisms. Mutations in mtDNA Coding and non-coding regions of mtDNA bear mutations and appear homoplasmic in nature. mtDNA mutations are associated with various diseases, especially those related with energy and metabolism such as neural and muscular syndromes (44). Both germline and somatic mutations of mtDNA have been reported in many cancers. Most of the mutations have been studied, and their roles in cancer development have been elucidated (45). Transition and transversion mutations of mtDNA contribute to human cancers, and most mutations are generally located in the all-important mtDNA-encoded genes. This was proved with clinical samples of several cancer types, where most prostate and thyroid cancers presented the mtDNA mutation 9821insA which affects nuclear gene expression. Upregulation of MMP-9 and downregulation of Col1a1 genes were reported in murine cybrid cells carrying mtDNA associated with skin tumors (46). Deletions in the control region were reported to be associated with lower levels of mtDNA in patients with hepatocellular carcinoma (47). Somatic mutations in the displacement-loop (D-loop), a 4977 bp deletion and low copy number of mtDNA were reported in patients with breast cancer (in 30, 47 and 63% of the tumors, respectively) when compared with normal tissues (48). The pervasive selective pressure for bone metastatic cells was observed in patients with prostate cancer that had metastasized to bones. Sequencing of mtDNA from tissues collected during autopsy showed a missense mutation at nucleotide position 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 (7 of 10 patients). It also revealed a tRNA Arg mutation at nucleotide position 10436 and a tRNA Thr mutation at nucleotide position 15928 in these patients (49). Somatic mtDNA mutations in complex I and its disassembly were associated with tumor formation in patients with benign renal oncocytoma. Kidney tissue samples in eight out of nine patients confirmed these results (50). In addition, undetectable or greatly reduced enzymatic activity of complex I was reported in 15 renal oncocytoma tissues and was associated with somatic mtDNA mutations (51). Inhibition of complex I by rotenone upregulates Akt phosphorylation and enhances tumorigenesis (52). Subsequently, complex I-disruptive mutations and nuclear chromosomal aberration were observed in pituitary adenomas (53). Differential impacts of complex I mutations are also observed in osteosarcoma progression. The homoplasmic mutations m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1 have different impacts on complex I functions. The m.3460G>A/MT-ND1 mutation reduces complex I activity, whereas m.3571insC/MT-ND1 and m.3243A>G/MT-TL1 mutations induce structural and functional modifications. These effects enhance the glycolytic metabolism and AMP-activated protein kinase activation (54). Respiratory function and tumorigenic potential of cancer cells were restored by mitochondrial genome acquisition; tumor cells lacking mtDNA, as a model of severe mtDNA damage, could acquire mtDNA from host cells of the tumor microenvironment. This process led to the gradual recovery of respirasome and complex II in primary tumors and of the metastatic potential (55). mtDNA microsatellite instability Mitochondrial genome mismatch-repair activity is maintained by YB-1 in human mitochondria (56). Mismatch-repair deficiency creates changes in the length of the microsatellite region of mtDNA, resulting in mtDNA microsatellite instability (mtMSI). Frameshift or missense mutations are more common features of colorectal carcinomas with mtMSI. DNA sequencing and single-strand conformation polymorphism analysis demonstrated the association between mtMSI and ND1 and ND5 genes mutations. Alterations in the polycytidine (C)n tract within a D-loop region have been detected in 44% of carcinoma patients. Frameshift mutations in a polyadenosine (A)8 or polycytidine (C)6 tract within ND genes were observed in the same population. These mutations caused truncated ND proteins at the C-terminus level (57). Further analysis revealed three mononucleotide repeat alterations, two missense mutations and one small (15 bp) deletion in the same genes (58). Nuclear MSI as well as mtMSI have been reported in Chinese HCC patients. The polymerase chain reaction-restriction fragment length polymorphism analysis of mtMSI found at least 1 locus in 11 out of 52 cases (21.2%), of which 7 cases reported 1 locus and 4 cases reported 2 loci. This study further revealed presence of mtMSI in D-loop in 10 cases (19.2%): 8 cases reported in the (C)n region and 2 cases in the (CA)n region. Furthermore, it also occurred in the coding region in five cases (9.6%), where the position of concomitant mtMSI locus was found in the D-loop in four out of the five cases (59). Alterations in D310 mononucleotide in the D-loop region were reported in 32 out of 95 (34%) colorectal cancer carcinoma patients (60). Helicobacter pylori infection has been associated with mtDNA mutations in gastric carcinoma cells (61). In addition, the positive correlation between H.pylori infection and mtMSI with increased interleukin-8 is reported in gastric carcinoma patients (62). Most of the mtMSI results in truncated proteins, which in turn affect mitochondrial metabolism and favor carcinogenesis. Mutations in tRNA encoded genes have been observed in gastric carcinoma, lung and thyroid cancers. These mutations generally do not have any roles in carcinogenesis (Supplementary Table S1, available at Carcinogenesis Online). Mutations in DNA polymerase-γ DNA polymerase-γ (DNA POLG) is an enzyme that synthesizes mtDNA. This enzyme has 3′-5′ exonuclease and polymerase activity. The nuclear genome-encoded POLG is responsible for DNA POLG. In the catalogue of somatic mutations in cancer (COSMIC) database (GRCh38·COSMIC v85), POLG (COSG795) is categorized as a tier 2 gene (meaning that it has a role in cancer but is less extensively reported) and is not curated under gene curation. Furthermore, this database reports missense and G>A substitutions in most cancers. Bleomycin (50 uM), SN-38, (5Z)-7-oxozeaenol, camptothecin, BEZ235, epothilone B, doxorubicin and vinblastine are drugs known to alter sensitivity to POLG mutation (63). Mutations in POLG cause depletion of and mutations in mtDNA. POLG nucleotide variants have been reported in colorectal cancer patients (64). Sequencing of all coding exons (2–23) and flanking intron/splice junctions of POLG showed mutations in most breast tumors (63% samples). This sequencing also identified a total of 17 mutations in the POLG. Mutations were reported in all three domains (T251I in the exonuclease domain, P587L in the linker region and E1143G in the polymerase domain), with concurrent depletion of mtDNA. Overall, mutated POLG decreases the mitochondrial membrane potential (ψ∆m) and increases ROS generation, which in turn promote tumorigenesis in breast cancers (65). A comprehensive race-based bioinformatics analyses indicated a 25-fold prevalence of mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) in European-Americans (allele frequency 0.03777) as compared with African-Americans (allele frequency 0.00151). These analyses also reported the prevalence of T251I and P587L missense variations in exonuclease and linker region of POLG1 in European-Americans. These variant expressions correlated with increased glucose consumption and decreased ATP production (66). Haplogroups mtDNA-based haplogroups play critical roles in cancer development. Most of them are strongly linked with ND1 dysfunction. However, conflicting outcomes were reported in some studies. One study reported that correlation between the G10398A polymorphism of haplogroup N and disease progression was strongly associated with breast and esophageal cancers (23), whereas the same was not significant in haplogroup M (67). Previously, a North American population-based study indicated that haplogroup U has 2- and 2.5-fold increased risk for prostate and renal cancer, respectively (22). Recent studies also indicate the predisposition of haplogroups for various cancers. Macrohaplogroup M and its subhaplogroup D5 present an increased risk of breast cancer development, and haplogroup D4a was associated with an increased risk of thyroid cancer in the Southern Chinese population (68). The genetic susceptibility to nasopharyngeal carcinoma was studied in the Chaoshan Han Chinese population, and variations in the mtDNA control region in haplogroup R9, specifically in its subhaplogroup F1, were shown to be associated with increased risk of nasopharyngeal carcinoma (69). A multiethnic cohort study also showed an association between the haplogroup T and the risk of colorectal cancer in European-Americans. This is mainly due to mtSNP in the NADH dehydrogenase 2 (MT-ND2) gene in complex I (24). However, a population-based study indicated no significant association between haplogroups and predisposition to prostate cancer in Korean patients (70). Metabolic reprogramming The ‘Warburg effect’ is one of the most remarkable metabolic characteristics of cancer cells. It is defined as an increase in the rate of glucose uptake and preferential production of lactate, even in the presence of O2. In the 1920s, Otto Warburg postulated this concept and proposed that cancer cells might originate from dysfunctional mitochondria (71). However, later studies indicated normal functioning of mitochondria in cancer cells (72). Mitochondrial uncoupling (the uncoupling of electron transport from ATP synthesis) plays a crucial role in the Warburg phenotype of tumor cells. Overexpression of uncoupling protein-2, inhibition of ROS accumulation and apoptosis were observed in the chemoresistant HCT116 cell line and its xenograft models. In addition, increased cell survival is achieved by altered amino terminal phosphorylation of p53 and induction of the glycolytic phenotype in these cells (73). Tumor microenvironment affects the Warburg effect and uncoupling in leukemia cells. Coculture of leukemia cells and bone marrow-derived mesenchymal stromal cells showed increased accumulation of lactate in the culture medium and reduction of mitochondrial membrane potential (ψ∆m) in both cells. Upregulation of uncoupling protein-2 expression was also observed in this coculture, whereas these effects were reversed in monocultures (74). The metabolic shift to aerobic glycolysis in cancer cells is mediated by mitochondrial uncoupling. Uncoupling protein-2 expression possibly affects the oxidation of other carbon sources, such as fatty acid and glutamine metabolism (75). Hexokinases (HKs) phosphorylate glucose during glycolysis, producing glucose-6-phosphate. The favorable roles of HKs for tumorigenesis have been elucidated, and upregulation is observed in several cancer cells. HKs interact with the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane (OMM) and use intramitochondrial ATP to phosphorylate glucose, thereby promoting a high rate of glycolysis (76). In addition, this interaction keeps VDAC in the open position, which counteracts OMM permeabilization. Furthermore, HKII-VDAC occupies the binding sites for Bax (a pro-apoptotic protein) on OMM, thereby preventing cytochrome c release and the induction of apoptosis (77). Mitochondrial metabolic reprogramming is regulated by oncogenes in cancer cells. Activation of PI3K/Akt signaling downstream of the receptor tyrosine kinase enhances glucose uptake and glycolysis (78). Rapid proliferation of cancer cells requires nucleotides, amino acids and fatty acids for macromolecular synthesis; Akt-stimulated glycolysis fulfills these requirements through the TCA cycle. Acetyl-CoA is required for the synthesis of lipids. These anabolic processes take place in the cytosol, but the conversion of pyruvate to acetyl-CoA is solely mitochondrial via the pyruvate dehydrogenase complex. Mitochondria-derived acetyl-CoA cannot be directly involved in cytosolic processes. Instead, citrate, an intermediated in the TCA cycle, is exported to the cytosol, where it is converted to acetyl-CoA by ATP-citrate lyase. Akt expression stimulates this reaction by phosphorylating ATP-citrate lyase (79). Additionally, oncogenic Myc enhances glutamine utilization by increasing the expression of glutaminase in cancer cells. Glutamine is used as nitrogen and/or carbon donor in proliferating cells (80) and is also used in the TCA cycle (81). The mitochondrial chaperone TRAP-1, which inhibits the succinate dehydrogenase (SDH) complex activity, is highly expressed in cancer cells. Downregulation of SDH (complex II) induces tumorigenesis by initiating the succinate-dependent stabilization of the pro-neoplastic transcription factor HIF1α (82). In addition, oncogenes and tumor suppressor genes affect the mitochondrial biogenesis status in cancer cells. c-Myc and K-Ras affect mitochondrial fusion and fission, respectively. Mitochondrial biogenesis is induced by mTOR through enhanced translation. In order to induce apoptosis, ROS generation induces BCl2 activation and p53 transcription (27) (Figure 4). Figure 4. View largeDownload slide Onco and tumor suppressor genes affect the mitochondrial status in cancer cells. c-Myc stimulates mitochondrial biogenesis, cell cycle progression and glycolysis through transcriptional regulation. In addition, c-Myc enhances mitochondrial fission and respiratory stress, which could result in increased oxidative signaling and ROS production. Mutations in K-Ras promote mitochondrial fission and mitophagy through a coordinated program of mitochondrial regulation and metabolic reprograming. Mitochondrial fission is induced through Drp1 phosphorylation by K-Ras. PI3K and PTEN mutations activate mTOR. Nutrient availability in cells also regulates mTOR activation. mTOR enhances mitochondrial biogenesis through transcription and translation. A high AMP/ATP ratio due to nutrient deficiency activates AMPK, which inhibits the mTOR activity. Loss of p53 thereby leads to survival of cancer cells. Direct interactions of p53 and Bcl-2 protein at the mitochondria favor apoptosis. Figure 4. View largeDownload slide Onco and tumor suppressor genes affect the mitochondrial status in cancer cells. c-Myc stimulates mitochondrial biogenesis, cell cycle progression and glycolysis through transcriptional regulation. In addition, c-Myc enhances mitochondrial fission and respiratory stress, which could result in increased oxidative signaling and ROS production. Mutations in K-Ras promote mitochondrial fission and mitophagy through a coordinated program of mitochondrial regulation and metabolic reprograming. Mitochondrial fission is induced through Drp1 phosphorylation by K-Ras. PI3K and PTEN mutations activate mTOR. Nutrient availability in cells also regulates mTOR activation. mTOR enhances mitochondrial biogenesis through transcription and translation. A high AMP/ATP ratio due to nutrient deficiency activates AMPK, which inhibits the mTOR activity. Loss of p53 thereby leads to survival of cancer cells. Direct interactions of p53 and Bcl-2 protein at the mitochondria favor apoptosis. Mitochondrial morphology Mitochondrial morphology is associated with mtDNA mutations and OXPHOS status in cancer cells. In general, human cancers show heterogeneous structural alterations in their mitochondria. Electron microscopy reveals numerous variations in mitochondrial morphology among the cancer cells, based on their origins (83). An accumulation of numerous irregular-shaped mitochondria with different degrees of electron density in the matrix was reported in Hürthle cell adenoma of thyroid (84). A decrease in the amount of cristal membranes with adaptation of circular appearance in the mitochondrial interior was reported in osteosarcoma cell lines (85). In contrast, a consistent increase in matrix density with condensation of the mitochondrial matrix and expansion of the cristal spaces was observed in HeLa cells grown in galactose (86). In human leukemia cells, mitochondria were abnormally swollen with pale matrix and disorganized cristae. These results indicate severe deficiency of mitochondrial respiration and activated glucose uptake with lactate accumulation (87). Moreover, mitochondrion-rich tumors were reported in five breast carcinoma patients (88). In gliomas, disarrangement of cristae and partial or total cristolysis was the most constant submicroscopic alteration observed and was associated with mitochondrial swelling (89). A recent study also indicates that mitochondrial alterations and energy metabolism changes are associated with radioresistant phenotypes in esophageal adenocarcinoma (90). The comparison of mitochondrial ultrastructure in primary ductal adenocarcinomas of the pancreas with normal pancreatic cells revealed that the malignant mitochondrial cells had a dense matrix and condensed configuration. Mitochondria with lucent-swelling matrix associated with disarrangement and distortion of cristae and partial or total cristolysis were reported in the same samples. Interestingly, 50% of mitochondria showed altered morphology in cancer cells. These structural alterations in mitochondria support the presence of hypoxia-sensitive and hypoxia-tolerant cancer cells (91). The aforementioned electron microscopic observations directly indicate the energetics of mitochondria in various cancer cells. These conditions could play important roles in therapeutic targeting of mitochondria. Targeting mitochondria for cancer therapy Mitochondria in cancer cells are structurally and functionally different from their counterparts in normal cells (eg. extensive metabolic reprogramming, defect in apoptosis and membrane permeability). In order to selectively target tumor cells and to rectify these mitochondrial dysfunctions, these processes have been targeted by mitochondrial specific drugs. Targeting the mitochondrial K+ channels [high membrane potential (ΔΨm) and low expression of the K+ channel (Kv.1.5)], mitochondrially associated HKII, oxidative phosphorylation complexes and mitochondrial ribosomes are some of the pharmaceutical approaches to induce cancer cell death. Table 2 shows some drugs targeting mitochondria in cancer therapies. In addition, some of the trends that have recently been developed for targeting mitochondria for cancer therapy are elaborated in this section. Table 2. Drugs targeting mitochondria and their mechanisms Drug Mechanism of action Studied cancer models Reference ABT-737 Dissociation of the Bcl-2/BAX complex and BAK-dependent, BIM-independent activation of the intrinsic apoptotic pathway. AML (127) ABT-263 Orally bioavailable Bad-like BH3 mimetic. Stimulation of Bax translocation, cytochrome c release and subsequent apoptosis. SCLC, leukemia and lymphoma (128) ABT-199 Specificity for Bcl-2 and no affinity for Bcl-XL. Sparing platelets by Bcl-2-dependent tumors. AML and CLL (129) Obatoclax Disruption of the interaction between BAK and MCL1. Induces the formation of an active Bak/Bax complex. AML and cholangiocarcinoma (130) Bax activation in cholangiocarcinoma. (131) Gossypol Simultaneous inhibition of Bcl-2, Bcl-XL, Bcl-W and MCL1. Colon cancer (132) Prostate cancer (133) Menadione (vitamin K3) AIF-mediated lethal redox stress. Osteosarcoma (134) β-Lapachone ROS overproduction, PARP1 hyperactivation and cell death. NSCLC (135) Gamitrinibs Antagonist of HSP90 ATPase activity. Breast cancer, CML and prostate cancer (136) Betulinic acid MPT pore opening, cardiolipin modification, inhibition of SCD-1 and cytochrome c release. Cervical cancer and lung cancer (137) Resveratrol ROS production and hyperpolarization of mitochondrial membrane, leading to apoptosis. Colon cancer (138) All-trans-retinoic acid MPT pore opening and inhibition of ANT. Cervical cancer (139) Drug Mechanism of action Studied cancer models Reference ABT-737 Dissociation of the Bcl-2/BAX complex and BAK-dependent, BIM-independent activation of the intrinsic apoptotic pathway. AML (127) ABT-263 Orally bioavailable Bad-like BH3 mimetic. Stimulation of Bax translocation, cytochrome c release and subsequent apoptosis. SCLC, leukemia and lymphoma (128) ABT-199 Specificity for Bcl-2 and no affinity for Bcl-XL. Sparing platelets by Bcl-2-dependent tumors. AML and CLL (129) Obatoclax Disruption of the interaction between BAK and MCL1. Induces the formation of an active Bak/Bax complex. AML and cholangiocarcinoma (130) Bax activation in cholangiocarcinoma. (131) Gossypol Simultaneous inhibition of Bcl-2, Bcl-XL, Bcl-W and MCL1. Colon cancer (132) Prostate cancer (133) Menadione (vitamin K3) AIF-mediated lethal redox stress. Osteosarcoma (134) β-Lapachone ROS overproduction, PARP1 hyperactivation and cell death. NSCLC (135) Gamitrinibs Antagonist of HSP90 ATPase activity. Breast cancer, CML and prostate cancer (136) Betulinic acid MPT pore opening, cardiolipin modification, inhibition of SCD-1 and cytochrome c release. Cervical cancer and lung cancer (137) Resveratrol ROS production and hyperpolarization of mitochondrial membrane, leading to apoptosis. Colon cancer (138) All-trans-retinoic acid MPT pore opening and inhibition of ANT. Cervical cancer (139) AIF, apoptosis-inducing factor; AML, acute myeloid leukemia; BAK, Bcl-2 homologous antagonist/killer; BAX, Bcl-2-associated X protein; Bcl-XL, B-cell lymphoma-extra-large; BID, BH3-interacting domain; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HSP90, heat shock protein 90, MCL1, ML1 myeloid cell leukemia 1; MPT, mitochondrial permeability transition; NSCLC, non-small cell lung cancer; PARP1, poly [ADP-ribose] polymerase1; SCD-1, steroyl-CoA-desaturase; SCLC, small cell lung cancer. View Large Table 2. Drugs targeting mitochondria and their mechanisms Drug Mechanism of action Studied cancer models Reference ABT-737 Dissociation of the Bcl-2/BAX complex and BAK-dependent, BIM-independent activation of the intrinsic apoptotic pathway. AML (127) ABT-263 Orally bioavailable Bad-like BH3 mimetic. Stimulation of Bax translocation, cytochrome c release and subsequent apoptosis. SCLC, leukemia and lymphoma (128) ABT-199 Specificity for Bcl-2 and no affinity for Bcl-XL. Sparing platelets by Bcl-2-dependent tumors. AML and CLL (129) Obatoclax Disruption of the interaction between BAK and MCL1. Induces the formation of an active Bak/Bax complex. AML and cholangiocarcinoma (130) Bax activation in cholangiocarcinoma. (131) Gossypol Simultaneous inhibition of Bcl-2, Bcl-XL, Bcl-W and MCL1. Colon cancer (132) Prostate cancer (133) Menadione (vitamin K3) AIF-mediated lethal redox stress. Osteosarcoma (134) β-Lapachone ROS overproduction, PARP1 hyperactivation and cell death. NSCLC (135) Gamitrinibs Antagonist of HSP90 ATPase activity. Breast cancer, CML and prostate cancer (136) Betulinic acid MPT pore opening, cardiolipin modification, inhibition of SCD-1 and cytochrome c release. Cervical cancer and lung cancer (137) Resveratrol ROS production and hyperpolarization of mitochondrial membrane, leading to apoptosis. Colon cancer (138) All-trans-retinoic acid MPT pore opening and inhibition of ANT. Cervical cancer (139) Drug Mechanism of action Studied cancer models Reference ABT-737 Dissociation of the Bcl-2/BAX complex and BAK-dependent, BIM-independent activation of the intrinsic apoptotic pathway. AML (127) ABT-263 Orally bioavailable Bad-like BH3 mimetic. Stimulation of Bax translocation, cytochrome c release and subsequent apoptosis. SCLC, leukemia and lymphoma (128) ABT-199 Specificity for Bcl-2 and no affinity for Bcl-XL. Sparing platelets by Bcl-2-dependent tumors. AML and CLL (129) Obatoclax Disruption of the interaction between BAK and MCL1. Induces the formation of an active Bak/Bax complex. AML and cholangiocarcinoma (130) Bax activation in cholangiocarcinoma. (131) Gossypol Simultaneous inhibition of Bcl-2, Bcl-XL, Bcl-W and MCL1. Colon cancer (132) Prostate cancer (133) Menadione (vitamin K3) AIF-mediated lethal redox stress. Osteosarcoma (134) β-Lapachone ROS overproduction, PARP1 hyperactivation and cell death. NSCLC (135) Gamitrinibs Antagonist of HSP90 ATPase activity. Breast cancer, CML and prostate cancer (136) Betulinic acid MPT pore opening, cardiolipin modification, inhibition of SCD-1 and cytochrome c release. Cervical cancer and lung cancer (137) Resveratrol ROS production and hyperpolarization of mitochondrial membrane, leading to apoptosis. Colon cancer (138) All-trans-retinoic acid MPT pore opening and inhibition of ANT. Cervical cancer (139) AIF, apoptosis-inducing factor; AML, acute myeloid leukemia; BAK, Bcl-2 homologous antagonist/killer; BAX, Bcl-2-associated X protein; Bcl-XL, B-cell lymphoma-extra-large; BID, BH3-interacting domain; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HSP90, heat shock protein 90, MCL1, ML1 myeloid cell leukemia 1; MPT, mitochondrial permeability transition; NSCLC, non-small cell lung cancer; PARP1, poly [ADP-ribose] polymerase1; SCD-1, steroyl-CoA-desaturase; SCLC, small cell lung cancer. View Large Targeting Mitochondria K+ channels Mitochondria in cancer cells exhibit high membrane potential (ΔΨm) and low expression of the K+ channel (Kv.1.5). These properties contribute to apoptosis resistance in cancer cells. It is postulated that targeting Kv1.5 would restore apoptosis susceptibility. Dichloroacetate is widely used for lactic acidosis treatment and is also known to target Kv 1.5. Normalization of Kv 1.5 by an NFAT1-dependent mechanism, inhibition of mitochondrial pyruvate dehydrogenase kinase, low ΔΨm, increased apoptosis and growth arrest of cancer cells have been reported in dichloroacetate-treated cancer cell lines (92). Induction of Bak/Bax-independent death of cancer cells was reported when Kv 1.3 was targeted, but in this case, the membrane-permeant inhibitors, such as Psora-4, PAP-1 and clofazimine, were used for the activation of the intrinsic apoptotic pathway. Intraperitoneal injection of clofazimine in an orthotopic melanoma B16F10 mouse model showed 90% reduction in tumor size (93). Targeting HKII at MOM Mitochondrially associated HKII plays a key role in the increased aerobic glycolysis of cancer cells (94). 2-deoxyglucose (2DG) and 3-bromopyruvate (3BP) are inhibitors of the HKII activity. 2DG competes with glucose for HKII and causes HKII-VDAC dissociation, inhibiting glycolysis and promoting the susceptibility of cancer cells to other forms of treatment (95). 3BP dissociates HKII from VDAC and also inhibits complex II, resulting in the depletion of ATP and cancer cell death in animal models (96). Plant hormone-derived jasmonate compounds also have a role in the detachment of HKII from MOM, and the cytotoxic effect (interaction with VDAC and cytochrome c release) of methyl jasmonate (MJ) has been presented in various cancer cell lines (murine melanoma B16, murine colon carcinoma CT26, murine B-cell leukemia BCL1 and human T lymphoblastic leukemia cell line Molt-4) (97). Targeting oxidative phosphorylation complexes Numerous compounds are known to target OXPHOS complexes, most of which aim at complex II for cancer cell destruction. Complex II has dual activity: as SDH and as succinate:ubiquinone reductase. Alpha-tocopheryl succinate (α-TOS; a selective anticancer drug) binds SDH and induces apoptosis in cancer cells. The mechanism and action of α-TOS, which interacts with the proximal and distal UbQ-binding site (QP and QR, respectively) of SDH, have been elucidated in CybL-mutant cells. It was proposed that electrons generated by α-TOS-targeted SDH result in the production of ROS (98). Lonidamine [LND, 1-(2, 4-dichlorobenzyl)-1H-indazole-3-carboxylic acid], an antitumor agent, promotes the accumulation of succinate in cancer cell lines. Furthermore, it inhibits succinate:ubiquinone reductase activity without fully repressing SDH activity (99). Thenoyltrifluoroacetone specifically binds SDH at the UbQ-binding site and causes cell death in a panel of chemoresistant neuroblastoma cell lines, a mechanism that is induced by cisplatin (100). Furthermore, inhibition of complex I (NADH dehydrogenase) by metformin (an antidiabetic drug) was shown in cancer cells. Metformin reduces blood glucose levels through the inhibition of mitochondrial glycerophosphate dehydrogenase (101). In cancer cells, exposure to metformin slows the cellular proliferation in the presence of glucose; upon glucose deprivation, it induces cell death. In addition, hypoxic activation of HIF1 is also reduced by metformin. Overexpression of the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 reverses the effects of the drug. The same effect was also observed in human cancer cells in mice (102). Earlier, a MEDLINE- and EMBASE-based systemic review indicated that metformin treatment might be associated with a significant reduction in the risk of cancer and cancer-related mortality (103), which was confirmed in a clinical-based study (104). Targeting mitochondrial ribosomes Mitochondria have their own ribosomes for protein synthesis. The sedimentation coefficient of mitoribosomes is 55S, arising from the existence of two subunits: a large (39S) and a small (28S) subunit (105). The structure of mitoribosomes shares some similarities with bacterial ribosomes and may therefore be targeted by antibiotics which are widely used to treat bacterial infections. An unbiased quantitative proteomics analysis of cancer stem cells indicates that >40 metabolic targets are upregulated, most of which are key enzymes and the proteins involved in oxidation, ketone metabolism and biogenesis of mitochondria (106). Another study in cancer stem cells of eight different types of cancer cells confirmed the anticancer effect of five classes of antibiotics: erythromycins, chloramphenicol, tetracyclines, glycyclines and pyrivinium pamoate (107). These classes of antibiotics inhibit protein synthesis via targeting either the large or the small subunit of bacterial ribosomes (108), except pyrivinium pamoate which inhibits the mitochondrial OXPHOS (109). Earlier clinical-based studies confirmed the advantage of using antibiotics for cancer treatment. Administration of azithromycin, in combination with paclitaxel and cisplatin, resulted in prolonged survival and decreased side effects in patients with stage III–IV non-small cell lung cancer (110). Interestingly, regression of ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (OAL) has been reported after doxycycline therapy for Chlamydophila psittaci (Cp) infection in nine patients (111), which was subsequently confirmed in another patient (112). Furthermore, a multicenter trial confirmed an objective response to doxycycline therapy in both Cp+ and Cp− OAL patients (113). Targeting apoptosis by nanotechnology Recent studies in nanotechnology focus on selective drug delivery to cancer cells. Targeting subcellular organelles is a major approach to improve therapy. Targeting mitochondria is difficult due to the chemical composition of the membranes and the strong negative membrane potential. In the past, numerous charged molecules were formulated, but poor pharmacokinetics (Pk) and biodistribution (bioD) profiles were observed in in vivo studies. However, alternative strategies have shown significant progress. To induce apoptosis, selective targeting of mitochondria and inhibition of thioredoxin reductase have been accomplished by Au (I) complexes of N-heterocyclic carbenes, and regression of the tumorigenic MDA-MB-231 cells was observed in vitro (114). In another study, the human breast cancer cell line Jimt-1 was exposed to gold nanoparticle (AuNP) conjugates formulated with cationic-modified poly (propylene imine) third generation dendrimers. Fluorescence and transmission electron microscopy analyses confirmed the direction, transfection and partial rupture of OMM by modified AuNP (115). Furthermore, a photodynamic therapy drug delivery and phototoxicity on/off nanosystem based on graphene oxide (NGO) has also been evaluated. NGO is modified with the integrin αvβ3 monoclonal antibody (mAb) for tumor targeting; to induce phototoxicity, the surface of the NGO is covered by pyropheophorbide-a (PPa) in conjugation with polyethylene-glycol. In vitro-based confocal fluorescence imaging, photodynamic treatment and cell viability assays have confirmed the effective targeting, receptor recognition and on/off control of PPa-NGO-mAb-based nanomaterial in the mitochondria of U87-MG and MCF7 cancer cells (116). Summary and conclusion Mitochondria act as ‘foe and friend’ in cancers. Mutations in mtDNA as well as in nDNA create a feasible cellular environment for tumorigenesis. Dysregulations in mitochondria-associated cellular functions contribute toward numerous vital factors for cancer development. In addition, mitochondria produce energy and metabolites for tumor growth. Generation of ROS by ETC also coalesces with essential factors for tumor development via hypoxia. In general, these effects are closely associated with each other. For instance, ROS accumulation causes mtDNA mutation and is associated with hypoxia and aerobic glycolysis. Moreover, mutations in the TCA cycle enzymes result in accumulation of metabolites that are widely used for cancer progression and metastasis. Alterations in the mitochondrial network are heterogeneous in various cancers. These alterations directly imply the mitochondrial energy status and are also linked with hypoxia-tolerant and hypoxia-sensitive cell phenotypes. For instance, cancer cells with mitochondrial defects or under hypoxic conditions could respond well to the therapeutic efficacy of glycolytic inhibitors, whereas cancer cells with active OXPHOS and hypoxic tolerance would require inhibition of mitochondrial respiration. Mitochondrial alterations in cancer cells are targeted by various approaches (Figure 3). Activation of pro-apoptotic as well as inhibition of antiapoptotic pathways are essential pharmaceutical strategies to target mitochondria. In addition, for mitochondrial ROS induction in cancer cells, several molecules which generally induce apoptosis have been used. Various peptides and molecules targeting mitochondria have been developed to alter cancer cell metabolism. Most of them are widely used in clinical levels. Despite the numerous drugs targeting mitochondria in cancer therapies, the treatment outcomes remain limited. Biological science has elucidated almost all mitochondria-related mechanisms, as well as revelation of mitochondrial pathologies. However, given the versatile roles of mitochondria in cancer cells, more mitochondria-based cancer studies are warranted, as these studies may reveal targeting molecules and pathways useful for cancer therapy. Funding This study was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2016R1D1A1B03935221; NRF-2017R1C1B5015034; NRF-2018R1D1A1B07050358). Conflict of Interest Statement: None declared. Abbreviations Abbreviations ATP adenosine triphosphate Bcl-2 B-cell lymphoma 2 D-loop displacement-loop ETC electron transport chain HIFs hypoxia-inducible factors HKs hexokinases mtDNA mitochondrial DNA mtMSI microsatellite instability nDNA nuclear DNA NGO nanosystem based on graphene oxide O2 oxygen OMM outer mitochondrial membrane OXPHOS oxidative phosphorylation PHDs prolyl hydroxylases ROS reactive oxygen species SDH succinate dehydrogenase TCA tricarboxylic acid VDAC voltage-dependent anion channel References 1. Hartwell L.H. et al. ( 1994 ) Cell cycle control and cancer . Science , 266 , 1821 – 1828 . Google Scholar Crossref Search ADS PubMed 2. Lee E.Y. et al. ( 2010 ) Oncogenes and tumor suppressor genes . Cold Spring Harb. Perspect. Biol. , 2 , a003236 . Google Scholar PubMed 3. Elmore S . ( 2007 ) Apoptosis: a review of programmed cell death . Toxicol. Pathol. , 35 , 495 – 516 . Google Scholar Crossref Search ADS PubMed 4. Evan G.I. et al. 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TI - Mitochondria in cancer: in the aspects of tumorigenesis and targeted therapy
JF - Carcinogenesis
DO - 10.1093/carcin/bgy148
DA - 2018-12-31
UR - https://www.deepdyve.com/lp/oxford-university-press/mitochondria-in-cancer-in-the-aspects-of-tumorigenesis-and-targeted-ML1vJWzu51
SP - 1419
VL - 39
IS - 12
DP - DeepDyve
ER -