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

Nicola Raule,1* Federica Sevini,1* Shengting Li,2 Annalaura Barbieri,1 Federica Tallaro,3 Laura Lomartire,1 Dario Vianello,1

Barbieri,1 Federica Tallaro,3 Laura Lomartire,1 Dario Alberto Montesanto,3 Jukka S. Moilanen,4 Vladyslav Bezrukov,5 H(cid:1) el(cid:3) ene Blanch(cid:1) e,6 Antti Hervonen,7 Kaare Christensen,8 Luca Deiana,9 Efstathios S. Gonos,10 Tom B. L. Kirkwood,11 Peter Kristensen,12 Alberta Leon,13 Pier Giuseppe Pelicci,14 Michel Poulain,15 Irene M. Rea,16 Jos(cid:3) e Remacle,17 Jean Marie Robine,18 Stefan Schreiber,19 Ewa Sikora,20 Peternella Eline Slagboom,21 Liana Spazzafumo,22 Maria Antonietta Stazi,23 Olivier Toussaint,24 James W. Vaupel,25 Giuseppina Kari Majamaa,4 Markus Perola,26 Thomas E. Johnson,27 Lars Bolund,2 Huanming Yang,2 Giuseppe Passarino3 and Claudio Franceschi1

Alberto Montesanto,3 Jukka S. Moilanen,4 Vladyslav Bezrukov,5 H(cid:1) el(cid:3) ene Blanch(cid:1) e,6 Antti Hervonen,7 Kaare Christensen,8 Luca Deiana,9 Efstathios S. Gonos,10 Tom B. L. Kirkwood,11 Peter Kristensen,12 Alberta Leon,13 Pier Giuseppe Pelicci,14 Michel Poulain,15 Irene M. Rea,16 Jos(cid:3) e Remacle,17 Jean Marie Robine,18 Stefan Schreiber,19

Summary

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 muta- tions 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.

Bi

hysics and Biocomplexity and Department of Experimental Pathology, C.I. G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, University of Bologna, Bologna

,Italy

BGI Shenzhen, Shenzhen

, China

Department of Cell Biology, University of Calabria, Rende

,Italy

Institute of Clinical Medicine, University of Oulu, Oulu University Hospital and MRC Oulu, Oulu

, Finland

Institute of Gerontology, Kiev,

,Ukraine

Centre Polymorphisme Humaine, Fondation Jean Dausset, Paris

, France

University of Tampere, Tampere

,Finland

Institute of Public Health, University of Southern Denmark, Odense

, Denmark

University of Sassari, Sassari

, Italy

National Hellenic Research Foundation, Athens

,Greece

School of Clinical Medical Sciences, Gerontology “Henry Wellcome”, University of Newcastle upon Tyne, Newcastle upon Tyne, NE

BZ,UK

University of Aarhus, Aarhus

,Denmark

Research & Innovation Soc.Coop. a r.l., Padova

,Italy

Research Centre of Demographic Management for Public UCL—G(cid:

)

AP, Louvain-la-Neuve,

Belgium

The Queen’s University Belfast, Belfast, BT

NN,UK

Eppendorf Array Technologies, SA—EAT Research and Development, Namur

,Belgium

University of Montpellier, Val d’Aurelle Cancer Research Center, Montpellier

,France

Kiel Center for Functional Genomics, University Hospital Schleswig Holstein, Kiel

,Germany

Key words: genetics of longevity; longevity; mitochondrial DNA; mtDNA sequencing; oxidative phosphorylation.

Introduction

Research on mitochondrial biology has underlined the central role played by the mitochondrion in a number of complex traits, including aging and metabolic and degenerative diseases. Mitochondria, due to their central position between energy uptake and energy production, are involved in a number of cellular processes such as heat production, apoptosis regulation, and cellular differentiation. In addition, mito- chondria are responsible for the production and the regulation of the most important by-product of the cellular metabolism, reactive oxygen species (ROS), which are widely considered to be one of the main causes of aging (for a review see Passarino et al., 2010; Wallace, 2010). Most of the proteins determining the biology of mitochondria

Correspondence

Giuseppe Passarino, Department of Cell Biology, University of Calabria, 87036, Rende, Italy. Tel.: +39 0984 492932; fax: +39 0984 492933; e-mail: g.passarino@unical.it and Claudio Franceschi, C.I.G. Interdepartmental Centre L.Galvani for Integrated Studies on Bioinformatics, BioPhysics and Biocomplexity and Department of Experimental Pathology, University of Bologna, 40126, Bologna, Italy. Tel.: +39 051 2094743; fax: +39 051 2094747; e-mail: claudio.franceschi@unibo.it

*F. Sevini and N. Raule equally contributed to the study.

ª 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits distribution and reproduction in any medium, provided the original work is properly cited.

Results