mtDNA mutations in human aging and longevity: controversies and new perspectives opened by high-throughput technologies.
The last 30 years of research greatly contributed to shed light on the role of mitochondrial DNA (mtDNA) variability in aging, although contrasting results have been reported, mainly due to bias regarding the population size and stratification, and to the use of analysis methods (haplogroup classification) that resulted to be not sufficiently adequate to grasp the complexity of the phenomenon. A 5-years European study (the GEHA EU project) collected and analyzed data on mtDNA variability on an unprecedented number of long-living subjects (enriched for longevity genes) and a comparable number of controls (matched for gender and ethnicity) in Europe. This very large study allowed a reappraisal of the role of both the inherited and the somatic mtDNA variability in aging, as an association with longevity emerged only when mtDNA variants in OXPHOS complexes co-occurred. Moreover, the availability of data from both nuclear and mitochondrial genomes on a large number of subjects paves the way for an evaluation at a very large scale of the epistatic interactions at a higher level of complexity. This scenario is expected to be even more clarified in the next future with the use of next generation sequencing (NGS) techniques, which are becoming applicable to evaluate mtDNA variability and, then, new mathematical/bioinformatic analysis methods are urgently needed. Recent advances of association studies on age-related diseases and mtDNA variability will also be discussed in this review, taking into account the bias hidden by population stratification. Finally, very recent findings in terms of mtDNA heteroplasmy (i.e. the coexistence of wild type and mutated copies of mtDNA) and aging as well as mitochondrial epigenetic mechanisms will also be discussed.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy; C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy. Electronic address: federica.sevini@unibo.it.
Federica
F
Sevini
Department of Biological, Geological and Environmental Sciences, Laboratory of Anthropology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; Department of Biological, Geological and Environmental Sciences, Centre for Genome Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Cristina
C
Giuliani
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy.
Dario
D
Vianello
Department of Physics and Astronomy, Viale Berti Pichat 6/2, 40126 Bologna, Italy.
Enrico
E
Giampieri
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy.
Aurelia
A
Santoro
C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy.
Fiammetta
F
Biondi
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy; C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy.
Paolo
P
Garagnani
Department of Biology, Ecology and Earth Science, University of Calabria, 87036 Rende, Italy.
Giuseppe
G
Passarino
Department of Biological, Geological and Environmental Sciences, Laboratory of Anthropology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; Department of Biological, Geological and Environmental Sciences, Centre for Genome Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Donata
D
Luiselli
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy; C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy.
Miriam
M
Capri
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy; C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy; IRCCS, Institute of Neurological Sciences of Bologna, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy; CNR, Institute of Organic Synthesis and Photoreactivity (ISOF), Via P. Gobetti 101, 40129 Bologna, Italy.
Claudio
C
Franceschi
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy; C.I.G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, Biophysics and Biocomplexity, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy.
Stefano
S
Salvioli
D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008136:Longevity / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
D004272:DNA, Mitochondrial
Epistasis; Heteroplasmy; Longevity; Mitochondrial DNA; Next generation sequencing; mtDNA mutations