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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

Lookup NU author(s): Emeritus Professor Thomas Kirkwood

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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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Author(s): Raule N, Sevini F, Li ST, Barbieri A, Tallaro F, Lomartire L, Vianello D, Montesanto A, Moilanen JS, Bezrukov V, Blanche H, Hervonen A, Christensen K, Deiana L, Gonos ES, Kirkwood TBL, Kristensen P, Leon A, Pelicci PG, Poulain M, Rea IM, Remacle J, Robine JM, Schreiber S, Sikora E, Slagboom PE, Spazzafumo L, Stazi MA, Toussaint O, Vaupel JW, Rose G, Majamaa K, Perola M, Johnson TE, Bolund L, Yang HM, Passarino G, Franceschi C

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2014

Volume: 13

Issue: 3

Pages: 401-407

Print publication date: 01/06/2014

Online publication date: 17/12/2013

Acceptance date: 14/11/2013

Date deposited: 03/09/2014

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell Publishing

URL: http://dx.doi.org/10.1111/acel.12186

DOI: 10.1111/acel.12186

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