F. Sevini and N. Raule equally contributed to the study.
The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific
Article first published online: 17 DEC 2013
© 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 use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 3, pages 401–407, June 2014
How to Cite
Raule, N., Sevini, F., Li, S., Barbieri, A., Tallaro, F., Lomartire, L., Vianello, D., Montesanto, A., Moilanen, J. S., Bezrukov, V., Blanché, H., Hervonen, A., Christensen, K., Deiana, L., Gonos, E. S., Kirkwood, T. B. L., Kristensen, P., Leon, A., Pelicci, P. G., Poulain, M., Rea, I. M., Remacle, J., Robine, J. M., Schreiber, S., Sikora, E., Eline Slagboom, P., Spazzafumo, L., Antonietta Stazi, M., Toussaint, O., Vaupel, J. W., Rose, G., Majamaa, K., Perola, M., Johnson, T. E., Bolund, L., Yang, H., Passarino, G. and Franceschi, C. (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, 13: 401–407. doi: 10.1111/acel.12186
- Issue published online: 23 MAY 2014
- Article first published online: 17 DEC 2013
- Manuscript Accepted: 14 NOV 2013
- Life Sciences, Genomics and Biotechnology for Health
- European Union's FP6. Grant Number: LSHM-CT-2004-503270
- European Union's Seventh Framework. Grant Numbers: FP7/2007-2011, 259679
- genetics of longevity;
- mitochondrial DNA;
- mtDNA sequencing;
- oxidative phosphorylation
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.