Mitochondrial DNA Mutations in Oncocytic Adnexal Lacrimal Glands of the Conjunctiva

Bartoletti-Stella, Anna

doi:10.1001/archophthalmol.2011.95

Cited by 16 publications

(7 citation statements)

References 6 publications

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“…Such application has allowed to update the haplogroup assignment taking into account the more detailed actual classification as well as to revise incorrect attribution. Examples of human mtDNA data revised upon the direct implementation of HmtDB tools are abundant in the recent literature (6,7,26,27). The query system helps researchers to easily retrieve data on variants not listed in other databases (e.g.…”

Section: Discussionmentioning

confidence: 99%

HmtDB, a genomic resource for mitochondrion-based human variability studies

Rubino¹,

Piredda²,

Calabrese³

et al. 2011

Nucleic Acids Research

101

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HmtDB (http://www.hmtdb.uniba.it:8080/hmdb) is a open resource created to support population genetics and mitochondrial disease studies. The database hosts human mitochondrial genome sequences annotated with population and variability data, the latter being estimated through the application of the SiteVar software based on site-specific nucleotide and amino acid variability calculations. The annotations are manually curated thus adding value to the quality of the information provided to the end-user. Classifier tools implemented in HmtDB allow the prediction of the haplogroup for any human mitochondrial genome currently stored in HmtDB or externally submitted de novo by an end-user. Haplogroup definition is based on the Phylotree system. End-users accessing HmtDB are hence allowed to (i) browse the database through the use of a multi-criterion ‘query’ system; (ii) analyze their own human mitochondrial sequences via the ‘classify’ tool (for complete genomes) or by downloading the ‘fragment-classifier’ tool (for partial sequences); (iii) download multi-alignments with reference genomes as well as variability data.

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Section: Discussionmentioning

confidence: 99%

HmtDB, a genomic resource for mitochondrion-based human variability studies

Rubino¹,

Piredda²,

Calabrese³

et al. 2011

Nucleic Acids Research

101

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“…Immunohistochemical (IHC) analysis with antibodies against NDUFB8 subunit of CI (Invitrogen, Milan, Italy) and HIF-1α (Upstate Biotech, Billerica, MA, USA) was performed as previously reported [47]. The semi-quantitative analysis of the stained sections was done by light-microscopy at 100× magnification.…”

Section: Methodsmentioning

confidence: 99%

Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells

et al. 2013

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BackgroundAerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift. This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. In this framework, the role of mitochondrial complex I is still debated, in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism. The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression.MethodsComplex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 (MT-ND1). Complex I re-assembly and function recovery, also in terms of NADH consumption, were assessed. Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice. Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1α (HIF-1α) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts.ResultsComplementation of a truncative mutation in the gene encoding MT-ND1, showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo, fostering cancer progression. Such trigger was mediated by HIF-1α, whose stabilization was regulated after recovery of the balance between α-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue.ConclusionRespiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells, allowing them to sustain tumor growth. Differently from other mitochondrial tumor suppressor genes, therefore, a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties, highlighting the prognostic values of such genetic markers in cancer.

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“…From this observation, as well as from studies in which the mitochondrial genome was screened for oncocytic cancer-specific genetic lesions such as small and large deletions, depletion, or point mutations (Tallini et al 1994;Maximo et al 1998Maximo et al , 2002Maximo and Sobrinho-Simoes 2000;Costa-Guda et al 2007;Gasparre et al 2007Gasparre et al , 2008Gasparre et al , 2009Mayr et al 2008;Zimmermann et al 2009;Porcelli et al 2010;Bartoletti-Stella et al 2011), it is now generally accepted that the genetic hallmark of the oncocytic phenotype is the occurrence of disruptive mtDNA mutations, particularly in complex I subunits. This holds true for virtually all types of oncocytic tumors analyzed to date (Gasparre et al 2007(Gasparre et al , 2008(Gasparre et al , 2009Porcelli et al 2010;Bartoletti-Stella et al 2011), and, inversely, association between the occurrence of disruptive mutations and that of oncocytic foci has been shown, for instance, in endometrial carcinoma (Guerra et al 2011). Within the plethora of disruptive mutations, both frameshift and pathogenic missense changes are included, which ultimately lead to complex I impairment in terms of function and/or assembly.…”

Section: Mtdna Mutations In Cancer: the Peculiar Case Of Oncocytic Tumentioning

confidence: 99%

Relevance of Mitochondrial Genetics and Metabolism in Cancer Development

Gasparre

Porcelli

Lenaz

et al. 2013

Cold Spring Harbor Perspectives in Biology

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Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of aketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1a (HIF1a). On the other hand, if complex I is partially defective, the levels of NAD þ may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1a, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.

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Mitochondrial DNA Mutations in Oncocytic Adnexal Lacrimal Glands of the Conjunctiva

Cited by 16 publications

References 6 publications

HmtDB, a genomic resource for mitochondrion-based human variability studies

HmtDB, a genomic resource for mitochondrion-based human variability studies

Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells

Relevance of Mitochondrial Genetics and Metabolism in Cancer Development

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