Enhanced tumorigenicity by mitochondrial DNA mild mutations
Entidad
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Editor
Impact JournalsFecha de edición
2015-03-30Cita
Oncotarget 6.15 (2015): 13628-13643ISSN
1949-2553Financiado por
This work was supported by the “Instituto de Salud Carlos III” [PI 10/0703 and PI13/00556 to R.G and PI 04/1001 to MAFM]; “Comunidad Autónoma de Madrid” [S2010/BMD-2402 to R.G and S2010/BMD-2359 to MQ); “Fundación Mutua Madrileña” [10.04.02.0064 to MAFM] and the Spanish Ministry of Economy and Competitiveness (grant SAF2013-46183-R to MQ). M.E.G. is a staff scientist at the Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Spain.Proyecto
Comunidad de Madrid. S2010/BMD-2402/MITOLAB; Comunidad de Madrid. S2010/BMD-2359/SKINMODEL; Gobierno de España. SAF2013-46183-RMaterias
Cancer; Mitochondria; MtDNA mutations; LHON; Retrograde signaling; MedicinaResumen
To understand how mitochondria are involved in malignant transformation
we have generated a collection of transmitochondrial cybrid cell lines on the same
nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants
with different degrees of pathogenicity. These include the severe mutation in the
tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber’s hereditary optic
neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A)
and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid
of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial
dysfunction do not produce tumors when injected in nude mice. By contrast cybrids
containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending
on OXPHOS dysfunction.
The differences in tumorigenicity correlate with an enhanced resistance to
apoptosis and high levels of NOX expression. However, the final capacity of the
different cybrid cell lines to generate tumors is most likely a consequence of a complex
array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial
dysfunction.
Our results demonstrate the essential role of mtDNA in tumorigenesis and explain
the numerous and varied mtDNA mutations found in human tumors, most of which
give rise to mild mitochondrial dysfunction
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Google Scholar:Cruz-Bermúdez, Alberto
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Vallejo, Carmen G.
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Vicente-Blanco, Ramiro J.
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Gallardo, María Esther
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Fernández-Moreno, Miguel Ángel
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Quintanilla, Miguel
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Garesse Alarcón, Rafael
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