Mitochondrial DNA

Overview of Mitochondria and role of mtDNA in Cancer

Image from Wikimedia Commons

Overview of Mitochondria: Mitochondria (plural of mitochondrion) are membrane-bound organelles (the cell's 'mini organs') found in nearly all cells which play a vital role as "cellular power plants" by generating adenosine triphosphate (ATP), used by cells as a source of chemical energy. Mitochondria also play a role in cellular signaling, cellular differentiation, cell death, control of the cell cycle and cell growth, and other roles. Mitochondria are unusual in that they contain their own DNA, whilst the rest of the human genome is concentrated in the nucleus of the cell. Also, Mitochondrial DNA is only inherited from mothers, whist the DNA in the cells nucleus is inherited from both mother and father.

The number of mitochondria in a cell varies according to the type of tissue; many cells have a single mitochondrion, but others can contain hundreds or even thousands of mitochondria. Mitochondrial proteins also vary depending on the type of tissue. Mitochondria are made up of compartments (see diagram) that carry out specialised roles.

Mitochondrial DNA (mtDNA) and Cancer: mtDNA has been linked carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. mtDNA lacks introns, so mutations tend to occur in coding sequences and it is thought that accumulation of these mutations may lead to tumor formation (Radpour et al, 2009). Research into of role of mtDNA mutations in cancer is advancing understanding of their functional role in carcinogenesis, value in diagnosis and monitoring, and potential therapeutic implications.

Mutations in mitochondrial genes are common in cancer, but they don't tend to inactivate mitochondrial energy metabolism as this would disadvantage the cancer cells ability to divide and proliferate. However, mutations may alter the bioenergetic and biosynthetic state of Mitochondria. "These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status" (Wallace, 2012)

Acknowledgements: Diagram of the structure of a mitochondrion from Wikimedia Commons under a Creative Commons CC0 license.

mtDNA Databases and Resources (3 links)

Recent Research Publications

Naz S, Wang M, Han Y, et al.
Enzyme-responsive mesoporous silica nanoparticles for tumor cells and mitochondria multistage-targeted drug delivery.
Int J Nanomedicine. 2019; 14:2533-2542 [PubMed] Free Access to Full Article Related Publications

Cheng G, Zhang Q, Pan J, et al.
Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis.
Nat Commun. 2019; 10(1):2205 [PubMed] Free Access to Full Article Related Publications
Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.

Li S, Li G, Zhang T, et al.
Co-SLD suppressed the growth of oral squamous cell carcinoma via disrupting mitochondrial function.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1746-1757 [PubMed] Related Publications
To evaluate the safety and efficacy of novel cobalt complex with sulindac (Co-SLD), the zebrafish and oral squamous cell carcinoma CAL27 were investigated in the present study. The developmental toxicity of Co-SLD ranging from 5 to 20 μM was determined by exposure to 3-144-h post-fertilization (hpf) zebrafish. Our data showed that Co-SLD did not cause to the appreciable toxicity at low concentration (5 and 10 μM). A remarkable toxicity was observed at high concentration (20 μM), including increased mortality and malformation, delayed hatchability, reduced heart rate as well as suppressed behaviour. With regard to the antitumor activity of Co-SLD, inhibited cell growth and migration capability were outstandingly observed in oral squamous cell carcinoma treated with 10 and 20 μM Co-SLD, which could be mainly attributed to the Co-SLD-elicited mitochondrial damage as marked by the depression of mitochondrial membrane potential, ROS accumulation and ATP depletion. Furthermore, administration of 10 μM Co-SLD was an optimal concentration not only to avoid the normal tissue toxicity, but also to enhance the killing of cancer cells via disrupting mitochondrial dysfunction. Taken together the above results demonstrated the desirable response of oral squamous cell carcinoma to Co-SLD.

Cai G, Yu W, Song D, et al.
Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors.
Eur J Med Chem. 2019; 174:236-251 [PubMed] Related Publications
STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.

Aras S, Maroun MC, Song Y, et al.
Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis.
BMC Cancer. 2019; 19(1):411 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Autoantibodies function as markers of tumorigenesis and have been proposed to enhance early detection of malignancies. We recently reported, using immunoscreening of a T7 complementary DNA (cDNA) library of breast cancer (BC) proteins with sera from patients with BC, the presence of autoantibodies targeting several mitochondrial DNA (mtDNA)-encoded subunits of the electron transport chain (ETC) in complexes I, IV, and V.
METHODS: In this study, we have characterized the role of Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1, also known as CHCHD2), identified on immunoscreening, in breast carcinogenesis. We assessed the protein as well as transcript levels of MNRR1 in BC tissues and in derived cell lines representing tumors of graded aggressiveness. Mitochondrial function was also assayed and correlated with the levels of MNRR1. We studied the invasiveness of BC derived cells and the effect of MNRR1 levels on expression of genes associated with cell proliferation and migration such as Rictor and PGC-1α. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype.
RESULTS: We identified a nuclear DNA (nDNA)-encoded mitochondrial protein, MNRR1, that was significantly associated with the diagnosis of invasive ductal carcinoma (IDC) of the breast by autoantigen microarray analysis. In focusing on the mechanism of action of MNRR1 we found that its level was nearly twice as high in malignant versus benign breast tissue and up to 18 times as high in BC cell lines compared to MCF10A control cells, suggesting a relationship to aggressive potential. Furthermore, MNRR1 affected levels of multiple genes previously associated with cancer metastasis.
CONCLUSIONS: MNRR1 regulates multiple genes that function in cell migration and cancer metastasis and is higher in cell lines derived from aggressive tumors. Since MNRR1 was identified as an autoantigen in breast carcinogenesis, the present data support our proposal that both mitochondrial autoimmunity and MNRR1 activity in particular are involved in breast carcinogenesis. Virtually all other nuclear encoded genes identified on immunoscreening of invasive BC harbor an MNRR1 binding site in their promoters, thereby placing MNRR1 upstream and potentially making it a novel marker for BC metastasis.

Chen W, Liu H, Wang T, et al.
Downregulation of AIF-2 Inhibits Proliferation, Migration, and Invasion of Human Glioma Cells via Mitochondrial Dysfunction.
J Mol Neurosci. 2019; 68(2):304-310 [PubMed] Related Publications
Glioma remains the leading cause of brain tumor-related death worldwide. Apoptosis inducing factor (AIF) is a family of mitochondrial oxidoreductases that play important roles in mitochondrial metabolism and redox control. AIF-1 has been demonstrated to exert cell-killing effect via apoptosis in cancer cells, whereas the role of AIF-2 in cancer cells has not been determined. This study aimed to investigate the role of AIF-2 in human glioma cells. We found that AIF-2 was upregulated in human glioma tissues and cell lines, especially in U251 cells. Downregulation of AIF-2 using specific siRNA (Si-AIF-2) significantly reduced cell proliferation, induced G1 cell cycle arrest and differently regulated the expression of cell cycle regulator proteins in U251 cells. In addition, the results of Matrigel invasion assay and live-cell tracking assay showed that knockdown of AIF-2 inhibited cell invasion and migration. The results of immunocytochemistry indicated that knockdown of AIF-2 significantly attenuated the nuclear translocation of AIF-1, which was confirmed by western blot analysis. Furthermore, downregulation of AIF-2 resulted in mitochondrial dysfunction in U251 cells, as evidenced by reduced mitochondrial membrane potential (MMP), mitochondrial complex I activity, and mitochondrial Ca

Zhang L, Li S, Wang R, et al.
Anti-tumor effect of LATS2 on liver cancer death: Role of DRP1-mediated mitochondrial division and the Wnt/β-catenin pathway.
Biomed Pharmacother. 2019; 114:108825 [PubMed] Related Publications
Large tumor suppressor 2 (LATS2), an important mediator of the cell apoptotic response pathway, has been linked to the progression of several cancers. Here, we described the molecular feature of LATS2 as a novel antitumor factor in liver cancer cells in vitro. Western blotting was used to detect the expression of LATS2 and its downstream factors. ELISA, immunofluorescence, and flow cytometry were used to evaluate the alterations of mitochondrial function in response to LATS2 overexpression. Adenovirus-loaded LATS2 and siRNA against DRP1 were transfected into liver cancer cells to overexpress LATS2 and knockdown DRP1 expression, respectively. The results of the present study demonstrated that overexpression of LATS2 was closely associated with more liver cancer cell death. Mechanistically, LATS2 overexpression increased the expression of DRP1, and DRP1 elevated mitochondrial division, an effect that was accompanied by mitochondrial dysfunction, including mitochondrial membrane potential reduction, mitochondrial respiratory complex downregulation, mitochondrial cyt-c release into the nucleus and mitochondrial oxidative injury. Moreover, LATS2 overexpression also initiated mitochondrial apoptosis, and this process was highly dependent on DRP1-related mitochondrial division. Molecular investigations demonstrated that LATS2 modulated DRP1 expression via the Wnt/β-catenin pathway. Inhibition of the Wnt/β-catenin pathway pregented LATS2-mediated DRP1 upregulation, ultimately sustaining mitochondrial function and cell viability in the presence of LATS2 overexpression. Altogether, the above data identify LATS2-Wnt/β-catenin/DRP1/mitochondrial division as a novel anticancer signaling pathway promoting cancer cell death, which might be an attractive therapeutic target for the treatment of hepatocellular carcinoma.

Rogers C, Erkes DA, Nardone A, et al.
Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation.
Nat Commun. 2019; 10(1):1689 [PubMed] Free Access to Full Article Related Publications
Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway.

Devi U, Singh M, Roy S, et al.
Activation of prolyl hydroxylase-2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF-1α/FASN in ER + breast cancer subtype.
Cell Biochem Funct. 2019; 37(4):216-227 [PubMed] Related Publications
The present study was undertaken to inquest the chemical activation of prolyl hydroxylase-2 for the curtailment of hypoxia-inducible factor-1α and fatty acid synthase. It was well documented that hypoxia-inducible factor-1α and fatty acid synthase were overexpressed in mammary gland carcinomas. After screening a battery of compounds, BBAP-2 was retrieved as a potential prolyl hydroxylase-2 activator and validates its activity using ER + MCF-7 cell line and n-methyl-n-nitrosourea-induced rat in vivo model, respectively. BBAP-2 was palpable for the morphological characteristics of apoptosis along with changes in the mitochondrial intergrity as visualized by acridine orange/ethidium bromide and JC-1 staining against ER + MCF-7 cells. BBAP-2 also arrest the cell cycle of ER + MCF-7 cells at G2/M phase. Afterward, BBAP-2 has scrutinized against n-methyl-n-nitrosourea-induced mammary gland carcinoma in albino Wistar rats. BBAP-2 restored the morphological architecture when screened through carmine staining, haematoxylin and eosin staining, and scanning electron microscopy. BBAP-2 also delineated the markers of oxidative stress favourably. The immunoblotting and mRNA expression analysis validated that BBAP-2 has a potentialty activate the prolyl hydroxylase-2 with sequential downregulating effect on hypoxia-inducible factor-1α and its downstream checkpoint. BBAP-2 also fostered apoptosis through mitochondrial-mediated death pathway. The present study elaborates the chemical activation of prolyl hydroxylase-2 by which the increased expression of HIF-1α and FASN can be reduced in mammary gland carcinoma.

Fernandez-Gil BI, Guerra-Librero A, Shen YQ, et al.
Melatonin Enhances Cisplatin and Radiation Cytotoxicity in Head and Neck Squamous Cell Carcinoma by Stimulating Mitochondrial ROS Generation, Apoptosis, and Autophagy.
Oxid Med Cell Longev. 2019; 2019:7187128 [PubMed] Free Access to Full Article Related Publications
Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 

Li X, Yang C, Shen H
Gentiopicroside exerts convincing antitumor effects in human ovarian carcinoma cells (SKOV3) by inducing cell cycle arrest, mitochondrial mediated apoptosis and inhibition of cell migration.
J BUON. 2019 Jan-Feb; 24(1):280-284 [PubMed] Related Publications
PURPOSE: Gentiopicroside is an important plant secondary metabolite and has been reported to exhibit tremendous pharmacological potential. In the present study we investigated the anticancer effects of gentiopicroside against ovarian SKOV3 cancer cells.
METHODS: Anticancer effects were determined by MTT assay. Apoptosis was investigated by DAPI and annexin V/propidium iodide (PI) double staining. Mitochondrial membrane potential (MMP) determination and cell cycle analysis were carried out by flow cytometry. Protein expression was examined by western blotting.
RESULTS: The results showed that gentiopicroside exerted anticancer effects on SKOV3 cancer cells in a dose-dependent manner. The IC50 of gentiopicroside was 20 µM against the SKOV3 cancer cells. The anticancer effects were mainly found to be due to loss of MMP and induction of apoptosis. The Bax/Bcl-2 expression ratio was also altered upon gentiopicroside treatment. Furthermore, gentiopicroside could arrest the SKOV3 cells in G2/M phase of the cell cycle and prevent their migration and invasion.
CONCLUSIONS: These results indicate that gentiopicroside could prove a potential lead molecule in the treatment and management of ovarian cancer.

Fang W, Ma Y, Wang J, et al.
In vitro and in vivo antitumor activity of neochlorogenic acid in human gastric carcinoma cells are complemented with ROS generation, loss of mitochondrial membrane potential and apoptosis induction.
J BUON. 2019 Jan-Feb; 24(1):221-226 [PubMed] Related Publications
PURPOSE: The main aim of the study was to evaluate in vitro and in vivo the anticancer and apoptotic effects of neochlorogenic acid in human gastric carcinoma cell death and the underlying mechanism of apoptosis induction, reactive oxygen species (ROS) production and loss of mitochondrial membrane potential (MMP), m-TOR/PI3K/AKT signalling pathway, cell migration and cell invasion suppression.
METHODS: Fluorescence microscopy using DAPI and annexin V/PI staining in combination with flow cytometry was used to study the apoptotic effects induced by neochlorogenic acid on gastric cancer cells. The effects on ROS and MMP were studied by flow cytometry. Western blot assay was used to evaluate the effects of neochlorogenic acid on m-TOR/PI3/Akt signaling pathway. To examine the anti-cancer activity of neochlorogenic acid in vivo, we used the nude mice xenograft model.
RESULTS: The results indicated that neochlorogenic acid exhibited an IC50 of 20 µM in these cells. The study also showed that apoptosis was due to loss of MMP and increased intracellular ROS production. Neochlorogenic acid downregulated the expression of key proteins of m-TOR/PI3/Akt signaling pathway. After 6 weeks of neochlorogenic acid administration to mice, the average tumor volumes and growth for the untreated control group were significantly higher than the treated groups.
CONCLUSION: Based on these results, we propose that neochlorogenic acid can be a prospective anti-cancer therapeutic lead for the management of human gastric carcinoma.

Ding Z, Chen Q, Xiong B, et al.
Angustifoline inhibits human colon cancer cell growth by inducing autophagy along with mitochondrial-mediated apoptosis, suppression of cell invasion and migration and stimulating G2/M cell cycle arrest.
J BUON. 2019 Jan-Feb; 24(1):130-135 [PubMed] Related Publications
PURPOSE: The prime objective of the present study was to investigate the anticancer properties of angustifoline against COLO-205 human colon cancer cells. Its effects on cell autophagy, apoptosis, cell invasion and cell migration, and cell cycle arrest were also evaluated in the current study.
METHODS: WST-1 assay was used to study cytotoxic effects of the compound on the cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and matrigel assay were carried out to study the effects of angustifoline on cell migration and cell invasion respectively. To confirm autophagy, we evaluated the expression of several autophagy-associated proteins using Western blot assay along with transmission electron microscopy (TEM).
RESULTS: The findings indicated that angustifoline induced dose- and time-dependent cytotoxicity in COLO-205 human colon cancer cells along with inhibiting cancer cell colony formation. Angustifoline-treated cells exhibited cell shrinkage along with distortion of the normal cell morphology. Angustifoline-treated cells were also arrested in the G2/M phase of the cell cycle, showing strong dose-dependence. The compound also led to inhibition of cell migration and cell invasion. The results showed that treatment of these cells led to generation of autophagic cell vesicles. Furthermore, it was observed that the expression of Beclin-1 and LC3-II proteins was significantly upregulated in the angustifoline-administered COLO-205 cells.
CONCLUSIONS: In brief, the present study hints towards the potent anticancer potential of the natural product angustifoline against COLO-205 human colon cancer cells with in depth mechanistic studies.

Sun MY, Wang DD, Sun J, et al.
The Zuo Jin Wan Formula increases chemosensitivity of human primary gastric cancer cells by AKT mediated mitochondrial translocation of cofilin-1.
Chin J Nat Med. 2019; 17(3):198-208 [PubMed] Related Publications
Resistance to cisplatin (DDP)-based chemotherapy is a major cause of treatment failure in human gastric cancer (GC). It is necessary to identify the drugs to re-sensitize GC cells to DDP. In our previous research, Zuo Jin Wan Formula (ZJW) has been proved could increase the mitochondrial apoptosis via cofilin-1 in a immortalized cell line, SGC-7901/DDP. Due to the immortalized cells may still difficult highly recapitulate the important molecular events in vivo, primary GC cells model derived from clinical patient was constructed in the present study to further evaluate the effect of ZJW and the underlying molecular mechanism. Immunofluorescent staining was used to indentify primary cultured human GC cells. Western blotting was carried out to detect the protein expression. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell apoptosis. ZJW inhibited proliferation and induced apoptosis in primary DDP-resistant GC cells. Notably, the apoptosis in GC cells was mediated by inducing cofilin-1 mitochondrial translocation, down-regulating Bcl-2 and up-regulating Bax expression. Surprisingly, the level of p-AKT protein was higher in DDP-resistant GC cells than that of the DDP-sensitive GC cells, and the activation of AKT could attenuate ZJW-induced sensitivity to DDP. These data revealed that ZJW can increase the chemosensitivity in DDP-resistant primary GC cells by inducing mitochondrial apoptosis and AKT inactivation. The combining chemotherapy with ZJW may be an effective therapeutic strategy for GC chemoresistance patients.

Jin M, Wang J, Ji X, et al.
MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2019; 38(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitochondrial Ca
METHODS: The effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway.
RESULTS: MCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca
CONCLUSIONS: Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca

Elliott IA, Dann AM, Xu S, et al.
Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.
Proc Natl Acad Sci U S A. 2019; 116(14):6842-6847 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

Wang FX, Liang JH, Zhang H, et al.
Mitochondria-Accumulating Rhenium(I) Tricarbonyl Complexes Induce Cell Death via Irreversible Oxidative Stress and Glutathione Metabolism Disturbance.
ACS Appl Mater Interfaces. 2019; 11(14):13123-13133 [PubMed] Related Publications
Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re

Yang K, Li Y, Tang Q, et al.
Synthesis, mitochondrial localization of fluorescent derivatives of cinnamamide as anticancer agents.
Eur J Med Chem. 2019; 170:45-54 [PubMed] Related Publications
Mitochondria are considered as a therapeutic target for new drug design toward all kinds of cancer. Hence in order to enhance the dosage in mitochondrial fraction of cinnamamides, the mitochondria-targeted derivatives were designed by the incorporation of cinnamamides into a fluorophore carrier of coumarin-3-carboxamide with a 1:1 stoichiometry. Using the amide linkers, twenty-one compounds were synthesized and the cytotoxicity against a panel of cancer cells (MCF-7, Hela, HepG2, HL-60) was tested. In particular, compound 18c displayed the potent cytotoxicity toward HL-60 leukaemia cells, which could quickly and efficiently entry into HL-60 cells and specifically localize within mitochondria. And 18c preferred enrichment in HL-60 cells than in PBMC normal cells, accounting for the higher toxicity to cancer cells than to normal cells. Moreover, the dissipations of mitochondrial membrane potential and enhancement of cellular ROS level were also preceded upon 18c treatment, leading to cell cycle arrest and apoptosis/necrosis in HL-60 cells. Besides, acted as a Michael acceptor, 18c initiated a thia-Michael addition reaction toward cysteamine (1:2 stoichiometry), detecting by the UV-Vis spectrum and HRMS analysis. This could result in the blue emission of 18c in mitochondria after the procedure of cell fixation, owing to the formation of covalent bond with mitochondrial thiols. Our study reported 18c might be useful for the further development into a mitochondria-targeted anti-leukemia agent and the Michael acceptor might be a versatile functional group.

Song IS, Jeong YJ, Jeong SH, et al.
Modulation of Mitochondrial ERβ Expression Inhibits Triple-Negative Breast Cancer Tumor Progression by Activating Mitochondrial Function.
Cell Physiol Biochem. 2019; 52(3):468-485 [PubMed] Related Publications
BACKGROUND/AIMS: Breast cancer is a clinically and molecularly heterogeneous disease. Patients with triple-negative breast cancer (TNBC) have poorer outcomes than those with other breast cancer subtypes due to lack of effective molecular targets for therapy. The present study aimed to the identification of estrogen receptor (ER)β as a novel mitochondrial target in TNBC cells, together with underlying mechanisms.
METHODS: Expression of ERβ in clinical breast samples were examined by qRT-PCR, immunohistochemistry and immunoblotting. Subcellular distribution and binding of ERβ-Grp75 was determined by confocal microscopic analysis, co-immunoprecipitation experiments, and limited-detergent extraction of subcellular organelles. The effect of mitocondrial ERβ(mitoERβ) overexpression on cell proliferation and cell cycle distribution were assessed CCK-8 assays and FACS. Mitochondrial ROS, membrane potential, and Ca²⁺ level were measured using the specific fluorescent probes Mito-Sox, TMRE, and Rhod-2AM. The tumorigenic effect of mitoERβ overexpression was assessed using an anchorage-independent growth assay, sphere formation and a mouse orthotopic xenograft model.
RESULTS: ERβ expression was lower in tumor tissue than in adjacent normal tissue of patients with breast cancer, and low levels of mitochondrial ERβ (mitoERβ) also were associated with increased tumor recurrence after surgery. Overexpression of mitoERβ inhibited the proliferation of TNBC cells and tumor masses in an animal model. Moreover, overexpression of mitoERβ increased ATP production in TNBC cells and normal breast MCF10A cells, with the latter completely reversed by mitoERβ knockdown in MCF10A cells. Grp75 was found to positively regulate ERβ translocation into mitochondria via a direct interaction. Coimmunoprecipitation and subcellular fractionation experiments revealed that ERβ-Grp75 complex is stable in mitochondria.
CONCLUSION: These results suggest that the up-regulation of mitoERβ in TNBC cells ensures proper mitochondrial transcription, activating the OXPHOS system to produce ATP. Studying the effects of mitoERβ on mitochondrial activity and specific mitochondrial gene expression in breast cancer might help predict tumor recurrence, inform clinical decision-making, and identify novel drug targets in the treatment of TNBC.

Wang D, Huang H, Zhou M, et al.
A thermoresponsive nanocarrier for mitochondria-targeted drug delivery.
Chem Commun (Camb). 2019; 55(28):4051-4054 [PubMed] Related Publications
Mitochondria emerge as an important target for cancer therapy. Herein, by taking advantage of the recently reported high temperature of mitochondria, a well-tuned thermoresponsive nanocarrier was developed for specifically delivering the anticancer drug, paclitaxel (PTX), to mitochondria in cancer cells. The temperature-dependent delivery of drugs to mitochondria represents a novel anticancer strategy.

Yang C, Hu R, Lu F, et al.
Traceable cancer cell photoablation with a new mitochondria-responsive and -activatable red-emissive photosensitizer.
Chem Commun (Camb). 2019; 55(26):3801-3804 [PubMed] Related Publications
A mitochondria-responsive and -activatable photosensitizer (PS), MPS, composed of a pyridinium cation as a mitochondria targeting group and a dibenzylideneacetone derivative with environment-sensitive emission properties as the ROS generator and self-efficacy tracer, is reported. This multifunctional PS offers a new strategy for traceable photodynamic ablation of cancer cells.

Jonsson M, Fjeldbo CS, Holm R, et al.
Mitochondrial Function of CKS2 Oncoprotein Links Oxidative Phosphorylation with Cell Division in Chemoradioresistant Cervical Cancer.
Neoplasia. 2019; 21(4):353-362 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
CDK regulatory subunit 2 (CKS2) has a nuclear function that promotes cell division and is a candidate biomarker of chemoradioresistance in cervical cancer. The underlying mechanisms are, however, not completely understood. We investigated whether CKS2 also has a mitochondrial function that augments tumor aggressiveness. Based on global gene expression data of two cervical cancer cohorts of 150 and 135 patients, we identified a set of genes correlated with CKS2 expression. Gene set enrichment analysis showed enrichment of mitochondrial cellular compartments, and the hallmarks oxidative phosphorylation (OXPHOS) and targets of the MYC oncogene in the gene set. By in situ proximity ligation assay, we showed that CKS2 formed complex with the positively correlated MYC target, mitochondrial single-stranded DNA binding protein SSBP1, in the mitochondrion of cervix tumor samples and HeLa and SiHa cervical cancer cell lines, indicating a role in mitochondrial DNA (mtDNA) replication and thereby OXPHOS. CDK1 was found to be part of the complex. Flow cytometry analyses of HeLa cells showed cell cycle regulation of the CKS2-SSBP1 complex consistent with mtDNA replication activity. Moreover, repression of mtDNA replication and OXPHOS by acute hypoxia decreased CKS2-SSBP1 complex abundance and expression of MYC targets. By immunohistochemistry, cytoplasmic CKS2 expression was found to add to the prognostic impact of nuclear CKS2 expression in patients, suggesting that the mitochondrial function promotes tumor aggressiveness. Our study uncovers a novel link between regulation of cell division by nuclear pathways and OXPHOS in the mitochondrion that involves CKS2 and promotes chemoradioresistance of cervical cancer.

Xu N, Hua Z, Ba G, et al.
The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo.
J Exp Clin Cancer Res. 2019; 38(1):118 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with poor survival. New treatment approaches are urgently needed to improve treatment efficacy in RMS patients. DMAMCL is a novel agent from Asteraceae family that has been tested in phase I clinical trials in adult glioma in Australia.
METHODS: Five RMS cell lines (RD, RH18, RH28, RH30 and RH41) were used. The in vitro anti-tumor effect of DMAMCL, alone or in combination with VCR or Epirubicin, was studied using MTS assay or IncuCyte-Zoom cell confluency assay, and further validated by xenograft-mouse model in vivo. Changes in caspase-3/7 activity, cell-cycle progression and generation of ROS after DMAMCL treatment were investigated. Bim mRNA expression was measured by RT-qPCR, and protein expressions of Bim and phosphorylated-NF-κB(p65) by Western blotting. Small interfering RNAs (siRNA) of Bim were used to study the role of Bim in DMAMCL-induced cell death.
RESULTS: In vitro, DMAMCL treatment induced a dose-dependent increase in cell death that could be blocked by pan-caspase-inhibitor-Z-VAD-fmk in five RMS cell lines. The percent of cells in SubG1 phase and activities of caspase-3/7 increased after DMAMCL treatment; The combination of DMAMCL with VCR or Epirubicin significantly increased cell death compared to each reagent alone. In vivo, DMAMCL(75 mg/kg or 100 mg/kg) inhibited tumor growth and prolonged survival of mice bearing xenograft RMS tumors (RD, RH18, RH30, RH41). Compared to treatment with DMAMCL or VCR, a combination of two reagents caused significant inhibition of tumor growth (RD, RH41), even after treatment termination. The expression of Bim increased at protein level after DMAMCL treatment both in vitro and in vivo. The expression of p-NF-κB(p65) had a transient increase and the generation of ROS increased after DMAMCL treatment in vitro. Transfection of Bim siRNA into RMS cells blocked the DMAMCL-induced increase of Bim and partially attenuated the DMAMCL-induced cell death.
CONCLUSION: DMAMCL had an anti-tumor growth effect in vitro and in vivo that potentially mediated by Bim, NF-κB pathway and ROS. A combination of DMAMCL with chemotherapeutic drugs significantly increased the treatment efficacy. Our study supports further clinical evaluation of DMAMCL in combination with conventional chemotherapy.

Malagrinò F, Zuhra K, Mascolo L, et al.
Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia.
Oxid Med Cell Longev. 2019; 2019:8102936 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
Hydrogen sulfide (H

Lin JJ, Huang CC, Su YL, et al.
Proteomics Analysis of Tangeretin-Induced Apoptosis through Mitochondrial Dysfunction in Bladder Cancer Cells.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 20/09/2019 Related Publications
Tangeretin is one of the most abundant compounds in citrus peel, and studies have shown that it possesses anti-oxidant and anti-cancer properties. However, no study has been conducted on bladder cancer cells. Bladder cancer has the second highest mortality rate among urological cancers and is the fifth most common malignancy in the world. Currently, combination chemotherapy is the most common approach by which to treat patients with bladder cancer, and thus identifying more effective chemotherapeutic agents that can be safely administered to patients is a very important research issue. Therefore, this study investigated whether tangeretin can induce apoptosis and identified the signaling pathways of tangeretin-induced apoptosis in human bladder cancer cells using two-dimensional gel electrophoresis (2DGE). The results of the study demonstrated that 60 μM tangeretin reduced the cell survival of a BFTC-905 bladder carcinoma cell line by 42%, and induced early and late apoptosis in the cells. In this study 2DGE proteomics technology identified 41 proteins that were differentially-expressed in tangeretin-treated cells, and subsequently LC⁻MS/MS analysis was performed to identify the proteins. Based on the functions of the differentially-expressed proteins, the results suggested that tangeretin caused mitochondrial dysfunction and further induced apoptosis in bladder cancer cells. Moreover, western blotting analysis demonstrated that tangeretin treatment disturbed calcium homeostasis in the mitochondria, triggered cytochrome

Wise JTF, Wang L, Alstott MC, et al.
Investigating the Role of Mitochondrial Respiratory Dysfunction during Hexavalent Chromium-Induced Lung Carcinogenesis.
J Environ Pathol Toxicol Oncol. 2018; 37(4):317-329 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
Hexavalent chromium [Cr(VI)] is a lung carcinogen and its complete mechanism of action remains to be investigated. Metabolic reprogramming of key energy metabolism pathways (e.g., increased anaerobic glycolysis in the presence of oxygen or "Warburg effect", dysregulated mitochondrial function, and lipogenesis) are important to cancer cell and tumor survival and growth. In our current understanding of Cr(VI)-induced carcinogenesis, the role for metabolic reprogramming remains unclear. In this study, we treated human lung epithelial cells (BEAS-2B) with Cr(VI) for 6 months and obtained malignantly transformed cells from an isolated colony grown in soft agar. We also used Cr(VI)-transformed cells from two other human lung cell lines (BEP2D and WTHBF-6 cells). Overall, we found that all the Cr(VI)-transformed cells had no changes in their mitochondrial respiratory functions (measured by the Seahorse Analyzer) compared with passaged-matched control cells. Using a xenograft tumor growth model, we generated tumors from these transformed cells in Nude mice. Using cells obtained from the xenograft tumor tissues, we observed that these cells had decreased maximal mitochondrial respiration, spare respiratory capacity, and coupling efficiency. These results provide evidence that, although mitochondrial dysfunction does not occur during Cr(VI)-induced transformation of lung cells, it does occur during tumor development.

Chen XY, Ren HH, Wang D, et al.
Isoliquiritigenin Induces Mitochondrial Dysfunction and Apoptosis by Inhibiting mitoNEET in a Reactive Oxygen Species-Dependent Manner in A375 Human Melanoma Cells.
Oxid Med Cell Longev. 2019; 2019:9817576 [PubMed] Article available free on PMC after 20/09/2019 Related Publications
The mitochondrial protein mitoNEET is a type of iron-sulfur protein localized to the outer membrane of mitochondria and is involved in a variety of human pathologies including cystic fibrosis, diabetes, muscle atrophy, and neurodegeneration. In the current study, we found that isoliquiritigenin (ISL), one of the components of the root of

Gong N, Ma X, Ye X, et al.
Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment.
Nat Nanotechnol. 2019; 14(4):379-387 [PubMed] Related Publications
Mitochondrial redox homeostasis, the balance between reactive oxygen species and antioxidants such as glutathione, plays critical roles in many biological processes, including biosynthesis and apoptosis, and thus is a potential target for cancer treatment. Here, we report a mitochondrial oxidative stress amplifier, MitoCAT-g, which consists of carbon-dot-supported atomically dispersed gold (CAT-g) with further surface modifications of triphenylphosphine and cinnamaldehyde. We find that the MitoCAT-g particles specifically target mitochondria and deplete mitochondrial glutathione with atomic economy, thus amplifying the reactive oxygen species damage caused by cinnamaldehyde and finally leading to apoptosis in cancer cells. We show that imaging-guided interventional injection of these particles potently inhibits tumour growth in subcutaneous and orthotopic patient-derived xenograft hepatocellular carcinoma models without adverse effects. Our study demonstrates that MitoCAT-g amplifies the oxidative stress in mitochondria and suppresses tumour growth in vivo, representing a promising agent for anticancer applications.

Galicia-Vázquez G, Aloyz R
Metabolic rewiring beyond Warburg in chronic lymphocytic leukemia: How much do we actually know?
Crit Rev Oncol Hematol. 2019; 134:65-70 [PubMed] Related Publications
Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the western world. CLL consists of the accumulation of malignant B-cells in the blood stream and homing tissues. Although treatable, this disease is not curable, and resistance or relapse is often present. In many cancers, the study of metabolic reprograming has uncovered novel targets that are already being exploited in the clinic. However, CLL metabolism is still poorly understood. The ability of CLL lymphocytes to adapt to diverse microenvironments is accompanied by modifications in cell metabolism, revealing the challenge of targeting the CLL lymphocytes present in all different compartments. Despite this, the study of CLL metabolism led to an ongoing clinical trial using glucose uptake and mitochondrial respiration inhibitors. In contrast, glutamine and fatty acid metabolism remain to be further exploited in CLL. Here, we summarize the present knowledge of CLL metabolism, as well as the metabolic influence of Myc, ATM and p53 on CLL lymphocytes.

Soukupová K, Rudolf E
Suppression of proliferation and activation of cell death by sodium selenite involves mitochondria and lysosomes in chemoresistant bladder cancer cells.
J Trace Elem Med Biol. 2019; 52:58-67 [PubMed] Related Publications
The specific effects of sodium selenite (selenite) on a chemoresistant human bladder cancer cell line RT-112/D21 were investigated during 72 h. Selenite at low concentration of 2.5 μmol (otherwise tolerated in normal urothelial cells UROtsa) suppressed growth and proliferation of the tested cancer cells via induced oxidative stress. Selenite further altered mitochondrial functions (i.e. decreased mitochondrial membrane potential, increased production of superoxide and reduced ATP synthesis), disrupted lysosomal membranes and activated autophagy. These changes in selenite-exposed cells ultimately resulted in their demise via necrosis and other cell death modality displaying heterotypic apoptotic and autophagic features.

Further References

Radpour R, Fan AX, Kohler C, et al.
Current understanding of mitochondrial DNA in breast cancer.
Breast J. 2009 Sep-Oct; 15(5):505-9 [PubMed] Related Publications
The recent surge in mitochondrial research has been driven by the identification of mitochondria-associated diseases and the role of mitochondria in apoptosis and aging. Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. As mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences. The subsequent accumulation of mutations may lead to tumor formation. By virtue of their clonal nature, high copy number and high frequent mutations may provide a powerful molecular biomarker for the detection of cancer. It has been suggested that the extent of mtDNA mutations might be useful in the prognosis of cancer outcome and/or the response to certain therapies. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in breast cancer, and offer some perspectives as to the emergence of mtDNA mutations, including their functional consequences in cancer development, diagnostic criteria, and therapeutic implications.

Wallace DC
Mitochondria and cancer.
Nat Rev Cancer. 2012; 12(10):685-98 [PubMed] Free Access to Full Article Related Publications
Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

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