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The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

N Raule 1 F Sevini 1 S Li 2 A Barbieri 1 F Tallaro 3 L Lomartire 1 D Vianello 1 A Montesanto 3 Js Moilanen 4 V Bezrukov 5 H Blanché 6 A Hervonen 7 K Christensen 8 L Deiana 9 Es Gonos 10 Tb Kirkwood 11 P Kristensen 12 A Leon 13 Pg Pelicci 14 M Poulain 15 Im Rea 16 J Remacle 17 Jean-Marie Robine 18 S Schreiber 19 E Sikora 20 Slagboom, P Eline 21 L Spazzafumo 22 Stazi, M Antonietta 23 O Toussaint 24 Jw Vaupel 25 G Rose 3 K Majamaa 4 M Perola 26 Te Johnson 27 L Bolund 2 H yang 2 G Passarino 3 C Franceschi 1 
Abstract : 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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N Raule, F Sevini, S Li, A Barbieri, F Tallaro, et al.. 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, Blackwell Publishing Ltd, 2014, 13 (3), pp.401-407. ⟨10.1111/acel.12186⟩. ⟨hal-03478927⟩

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