Mitochondrial dysfunction in cancer

Modica-Napolitano, Josephine S.; Singh, Keshav K.

doi:10.1016/j.mito.2004.07.027

Cited by 276 publications

(219 citation statements)

References 72 publications

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“…2,22-24 Thus, mtDNA is extremely susceptible to ROS produced in the mitochondria. Consistent with this observation, mutation in mtDNA has been reported in all cancers examined to date 23,24 and in tissues during the normal process of aging. 25 Our results presented in this paper establish an intracellular link between the two major ROS producers: mitochondria and the Nox1 enzyme.…”

Section: Discussionsupporting

confidence: 71%

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

Desouki¹,

Kulawiec²,

Bansal³

et al. 2005

Cancer Biology & Therapy

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152

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Reactive oxygen species (ROS) function as cellular switches for signaling cascade involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contribute to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (ρ 0 ) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into ρ 0 cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that ρ 0 cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.

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Section: Discussionsupporting

confidence: 71%

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

Desouki¹,

Kulawiec²,

Bansal³

et al. 2005

Cancer Biology & Therapy

Self Cite

152

160

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“…Given the central roles of mitochondria in the regulation of fundamental cellular functions and bioenergetics, it is not surprising that these organelles have been implicated in multiple aspects of cancer development and tumor progression. Several lines of evidence support the hypothesis that cancer is primarily a disease of energy metabolism, and mitochondrial dysfunction has been found to be associated with the development of several human cancers (17,18). Cancer cells often exhibit some type of mitochondrial dysfunction, including mitochondrial DNA mutations, alterations in energy metabolism, elevated reactive oxygen species (ROS) generation, and increased mitochondrial membrane potential (MMP).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 98%

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA-depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. Hepatocellular carcinoma (HCC)2 is the most common and severe form of liver cancer, accounting for about 80 -90% of primary liver cancers and 5% of all human cancers. More than 600,000 deaths are attributed to HCC every year with 2:1 ratio for men versus women (1, 2). HCC is a primary cancer of hepatocytes that most typically occurs in the setting of known risk factors, including cirrhosis and chronic hepatitis B virus or hepatitis C virus infections (2, 3), although recently, several lines of evidence suggest that type 2 diabetes is also an independent risk factor for HCC development (4). HCC is an aggressive tumor and represents a major health problem as its incidence is increasing. Systemic chemotherapies have proven ineffective against advanced HCC, so it typically leads to death within 6 -20 months (5). Hepatocarcinogenesis is a multistep process involving inflammation, hyperplasia, and dysplasia that finally leads to malignant transformation. In recent years, mitochondria have been found to provide a novel targeting site for new anticancer drugs (known as "mitocans") that ca...

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“…Broadly, these can originate from either enhancing signals that directly increase glycolysis or from inhibiting energy metabolism by the mitochondria, rendering glycolysis the major source of ATP. Glycolytic enzymes are induced by oncogenes (Dang and Semenza, 1999;Plas and Thompson, 2005) or by the hypoxia-inducible transcription factor (HIF) (Maxwell, 2005a), whereas oxidative phosphorylation can be inhibited by mutations in mitochondrial DNA (Carew and Huang, 2002;Modica-Napolitano and Singh, 2004) or a dysfunctional TCA cycle owing to loss of function of mitochondrial tumour suppressor genes (Eng et al, 2003;Gottlieb and Tomlinson, 2005). This review focuses on a newly discovered biochemical link between the loss of mitochondrial tumour suppressors and the induction of glycolysis by the HIF pathway.…”

Section: Enhanced Glycolysis In Cancer Cellsmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Mitochondrial dysfunction in cancer

Cited by 276 publications

References 72 publications

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

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