A role for mitochondrial enzymes in inherited neoplasia and beyond

Eng, Charis; Kiuru, Maija; Fernandez, Magali; Aaltonen, Lauri A.

doi:10.1038/nrc1013

Cited by 355 publications

(278 citation statements)

References 55 publications

Supporting

Mentioning

271

Contrasting

Unclassified

Order By: Relevance

“…Mutations in the nuclear-encoded complex I subunits may account for the percentage of oncocytic cases in which mitochondrially encoded complex I subunits were not mutated; hence, the percentage of complex I mutations in oncocytic tumors could be underestimated. In fact, it has been shown that some types of hereditary tumors are characterized by mitochondrial defects (31). The presence of germ-line changes in mitochondria-related genes and their potential involvement in oncocytic tumor development further suggests a complex interplay between nuclear and mitochondrially encoded genes in promoting the oncocytic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Gasparre

Porcelli²,

Bonora

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

254

208

View full text Add to dashboard Cite

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P ‫؍‬ 0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.oncocytic tumors ͉ heteroplasmy ͉ homoplasmy ͉ damaging mutation ͉ microenvironment

show abstract

Section: Discussionmentioning

confidence: 99%

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Gasparre

Porcelli²,

Bonora

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

254

208

View full text Add to dashboard Cite

show abstract

“…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%

“…As many of the genetic aspects of mitochondrial tumour suppressor genes have been discussed in several recent extensive reviews (Baysal, 2003;Eng et al, 2003;Favier et al, 2005;Gottlieb and Tomlinson, 2005), only a brief history of the field will be given and more current data will be covered in this review. In particular, attention will be given to recent findings concerning the potential mechanisms of tumorigenesis in SDH and FH-linked tumours.…”

Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

View full text Add to dashboard Cite

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.

show abstract

“…Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations 2 . The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/ extrusion.…”

mentioning

confidence: 99%

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Miao²,

Lin³

et al. 2004

Nature

749

806

View full text Add to dashboard Cite

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism 1 . Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations 2 . The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/ extrusion. Here we show that GPR91 (ref.3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to a-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and a-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure 5,6 .In a search for natural ligands for orphan GPCRs, we tested extracts from various animal tissues for their ability to evoke an increase in intracellular Ca 2þ concentration ([Ca 2þ ] i ) using the aequorin assay 7 . We found that fractions from pig kidney extracts specifically activated cells expressing GPR91 (Fig. 1a). GPR91 is an orphan GPCR highly expressed in the kidney and shares 33% amino acid identity with GPR99/GPR80 (refs 4, 8). On the basis of their homology with the purinergic receptor P2Y1, nucleotide ligands were predicted for GPR91 and GPR99 (ref. 4). However, the GPR91 ligand activity in pig kidney extracts was resistant to various stringent treatments including alkaline phosphatase, peptidase, and hydrolysis in 6 M HCl at 100 8C. Accordingly, the supposition that GPR91 might be activated by a nucleotide or peptide ligand was unlikely. We purified the natural ligand for GPR91 by ion-exchange, size-exclusion and reversed-phase fast performance liquid chromatography/high-performance liquid chromatography (Fig. 1a).A major molecular ion [M þ H] þ at m/z 119.2 was observed by mass spectrometry (Fig. 1b). 1 H NMR analysis revealed a single type of proton in the highly purified GPR91 ligand (Fig. 1c). 13 C NMR analysis further suggested the presence of -CH 2 -(methylene) and ¼C¼O (carbonyl) groups (Fig. 1d). Combined with mass spectrometry results and the biochemical properties of the ligand, the purified GPR91 ligand was predicted and confirmed to be succinic acid (Fig. 1c, d).Commercially obtained succinate (the physiological form of succinic acid) increased [Ca 2þ ] i dose-dependently in the aequorin assay (Fig. 2a). Succinate also activated mouse and rat orthologues of GPR91 (Fig. 2a). The succinate-induced increase in [Ca 2þ ] i was further confirmed with a fluorimetric imaging plate reader (FLIPR) system in the 293-hGP...

show abstract

A role for mitochondrial enzymes in inherited neoplasia and beyond

Cited by 355 publications

References 55 publications

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Contact Info

Product

Resources

About