title: The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific.
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.
authors.affiliation: BioPhysics and Biocomplexity and Department of Experimental Pathology, C.I. G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, University of Bologna, Bologna, 40126, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Raule
authors.forename: Federica
authors.initials: F
authors.lastname: Sevini
authors.forename: Shengting
authors.initials: S
authors.lastname: Li
authors.forename: Annalaura
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authors.lastname: Barbieri
authors.forename: Federica
authors.initials: F
authors.lastname: Tallaro
authors.forename: Laura
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authors.lastname: Lomartire
authors.forename: Dario
authors.initials: D
authors.lastname: Vianello
authors.forename: Alberto
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authors.lastname: Montesanto
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.forename: Vladyslav
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authors.lastname: Bezrukov
authors.forename: Hélène
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authors.lastname: Blanché
authors.forename: Antti
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authors.lastname: Hervonen
authors.forename: Kaare
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authors.forename: Luca
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authors.forename: Efstathios S
authors.initials: ES
authors.lastname: Gonos
authors.forename: Tom B L
authors.initials: TB
authors.lastname: Kirkwood
authors.forename: Peter
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authors.lastname: Kristensen
authors.forename: Alberta
authors.initials: A
authors.lastname: Leon
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Michel
authors.initials: M
authors.lastname: Poulain
authors.forename: Irene M
authors.initials: IM
authors.lastname: Rea
authors.forename: Josè
authors.initials: J
authors.lastname: Remacle
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Robine
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Ewa
authors.initials: E
authors.lastname: Sikora
authors.forename: Peternella
authors.initials: P
authors.lastname: Eline Slagboom
authors.forename: Liana
authors.initials: L
authors.lastname: Spazzafumo
authors.forename: Maria
authors.initials: M
authors.lastname: Antonietta Stazi
authors.forename: Olivier
authors.initials: O
authors.lastname: Toussaint
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rose
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Johnson
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000369:Aged, 80 and over; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D009154:Mutation; D010085:Oxidative Phosphorylation
chemical_list: D004272:DNA, Mitochondrial
keywords: genetics of longevity; longevity; mitochondrial DNA; mtDNA sequencing; oxidative phosphorylation