TY - JOUR
T1 - The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific
AU - Raule, Nicola
AU - Sevini, Federica
AU - Li, Shengting
AU - Barbieri, Annalaura
AU - Tallaro, Federica
AU - Lomartire, Laura
AU - Vianello, Dario
AU - Montesanto, Alberto
AU - Moilanen, Jukka S.
AU - Bezrukov, Vladyslav
AU - Blanché, Hélène
AU - Hervonen, Antti
AU - Christensen, Kaare
AU - Deiana, Luca
AU - Gonos, Efstathios S.
AU - Kirkwood, Tom B.L.
AU - Kristensen, Peter
AU - Leon, Alberta
AU - Pelicci, Pier Giuseppe
AU - Poulain, Michel
AU - Rea, Irene M.
AU - Remacle, Josè
AU - Robine, Jean Marie
AU - Schreiber, Stefan
AU - Sikora, Ewa
AU - Eline Slagboom, Peternella
AU - Spazzafumo, Liana
AU - Antonietta Stazi, Maria
AU - Toussaint, Olivier
AU - Vaupel, James W.
AU - Rose, Giuseppina
AU - Majamaa, Kari
AU - Perola, Markus
AU - Johnson, Thomas E.
AU - Bolund, Lars
AU - Yang, Huanming
AU - Passarino, Giuseppe
AU - Franceschi, Claudio
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
KW - Genetics of longevity
KW - Longevity
KW - Mitochondrial DNA
KW - MtDNA sequencing
KW - Oxidative phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=84901209263&partnerID=8YFLogxK
U2 - 10.1111/acel.12186
DO - 10.1111/acel.12186
M3 - Journal article
C2 - 24341918
AN - SCOPUS:84901209263
SN - 1474-9718
VL - 13
SP - 401
EP - 407
JO - Aging Cell
JF - Aging Cell
IS - 3
ER -