Raule, Nicola and Sevini, Federica and Li, Shengting and Barbieri, Annalaura and Tallaro, Federica and Lomartire, Laura and Vianello, Dario and Montesanto, Alberto and Moilanen, Jukka S. and Bezrukov, Vladyslav and Blanché, Hélène and Hervonen, Antti and Christensen, Kaare and Deiana, Luca and Gonos, Efstathios S. and Kirkwood, Tom B. L. and Kristensen, Peter and Leon, Alberta and Pelicci, Pier Giuseppe and Poulain, Michel and Rea, Irene Maeve and Remacle, José and Robine, Jean Marie and Schreiber, Stefan and Sikora, Ewa and Slagboom, Peternella Eline and Spazzafumo, Liana and Stazi, Maria Antonietta and Toussaint, Olivier and Vaupel, James W. and Rose, Giuseppina and Majamaa, Kari and Perola, Markus and Johnson, Thomas E. and Bolund, Lars and Yang, Huanming and Passarino, Giuseppe and Franceschi, Claudio (2014) The Co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. Aging cell, Vol. 13 (3), p. 401-407. ISSN 1474-9718. eISSN 1474-9726. Article.
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To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.
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