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.

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

RAULE, NICOLA;SEVINI, FEDERICA;BARBIERI, ANNALAURA;LOMARTIRE, LAURA;VIANELLO, DARIO;FRANCESCHI, CLAUDIO
2014

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.
Nicola Raule;Federica Sevini;Shengting Li;Annalaura Barbieri;Federica Tallaro;Laura Lomartire;Dario Vianello;Alberto Montesanto;Jukka S. Moilanen;Vladyslav Bezrukov;Hélène Blanché;Antti Hervonen;Kaare Christensen;Luca Deiana;Efstathios S. Gonos;Tom B. L. Kirkwood;Peter Kristensen;Alberta Leon;Pier Giuseppe Pelicci;Michel Poulain;Irene M. Rea;Josè Remacle;Jean Marie Robine;Stefan Schreiber;Ewa Sikora;Peternella Eline Slagboom;Liana Spazzafumo;Maria Antonietta Stazi;Olivier Toussaint;James W. Vaupel;Giuseppina Rose;Kari Majamaa;Markus Perola;Thomas E. Johnson;Lars Bolund;Huanming Yang;Giuseppe Passarino;Claudio Franceschi
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acel0013-0401-sd1.pdf

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Descrizione: Fig. S1 Scatterplot of the first two principal component scores based on the 229 SNPs (MAF > 0.01) identified in the 1291 mtDNA analyzed sequences.
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Descrizione: Table S1. a and b. Haplogroup distribution in males and females.
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Descrizione: Table S2. List of all the mutations identified in our sample by the complete mtDNA sequencing.
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Descrizione: Table S6. Modified primer pairs for complete resequencing.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/216464
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