Gasparre G, Hervouet E, de Laplanche E, Demont J, Pennisi LF, Colombel M et al.. Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma. Hum Mol Genet 17: 986-995

Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy.
Human Molecular Genetics (Impact Factor: 6.39). 05/2008; 17(7):986-95. DOI: 10.1093/hmg/ddm371
Source: PubMed


Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (CI, NADH-ubiquinone oxidoreductase). In this work total sequencing of mtDNA showed that 9/9 tumors harbored point mutations in mtDNA, seven in CI genes, one in complex III, and one in the control region. 7/8 mutations were somatic. All tumors were somatically deficient for CI. The clonal amplification of mutated mtDNA in 8/9 tumors demonstrates that these alterations are selected and therefore favor or trigger growth. No nuclear DNA rearrangement was detected beside mtDNA defects. We hypothesize that functional deficiency of the oxidative phosphorylation CI could create a loop of amplification of mitochondria during cell division, impair substrates oxidation and increase intermediary metabolites availability.

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    • "Mouse cells harbouring a high mutation load in cytochrome b, a mitochondrially encoded subunit of complex III, have been shown to be deficient in both complex III and complex I (Acin-Perez et al 2004). Homozygous loss-offunction mutations in cytochrome b have been reported in human oncocytic tumours with a complete loss of complex I (Gasparre et al 2008; Zimmermann et al 2011), which is clear evidence that assembled complex III is necessary for complex I assembly and supercomplex formation. Also a mutation in the UQCRC2 subunit resulted in aberrant supercomplex formation and deficiency of complex I in addition to complex III (Miyake et al 2013). "
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    ABSTRACT: Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.
    Full-text · Article · Mar 2015 · Journal of Inherited Metabolic Disease
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    • "An ND5 gene frameshift mutation, which was found to be homoplasmic in a human oncocytoma tumor, was present at low-heteroplasmy levels in the normal tissues of the patient and his two sisters. Thus, this deleterious mutation was silently transmitted through the maternal lineage (Gasparre et al. 2008). Hence, classical concepts of genotype – phenotype associations and their interaction with selection are violated by mtDNA genetics. "
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    ABSTRACT: The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common "complex" diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these "heteroplasmic" mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease.
    Full-text · Article · Nov 2013 · Cold Spring Harbor perspectives in biology
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    • "Conversely, OXPHOS inhibition can play a causal role in tumorigenesis. Inactivating mutations in mitochondrial DNA (mtDNA) genes encoding for subunits of ETC complexes I and III were found associated with renal oncocytomas (Gasparre et al., 2008) as well as thyroid and prostate cancers (Abu-Amero et al., 2005; Petros et al., 2005). However, these mutations are confined to a small set of neoplasms, and the lack of clear-cut molecular mechanisms hampers the definition of whether OXPHOS inhibition as such can play a general tumorigenic role. "
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    ABSTRACT: We report that the mitochondrial chaperone TRAP1, which is induced in most tumor types, is required for neoplastic growth and confers transforming potential to noncancerous cells. TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex II of the respiratory chain. The respiratory downregulation elicited by TRAP1 interaction with SDH promotes tumorigenesis by priming the succinate-dependent stabilization of the proneoplastic transcription factor HIF1α independently of hypoxic conditions. These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target.
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