Age-Linked Changes in the Genotype and Phenotype of Mitochondria

Gadaleta, Maria Nicola; Kadenbach, Bernhard; Lezza, Angela Maria Serena; Reith, Annette; Cantatore, Palmiro; Boffoli, Domenico; Papa, Sergio

doi:10.1007/978-1-4615-4843-0_28

Cited by 5 publications

(2 citation statements)

References 136 publications

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“…19 However, the low number of mutant molecules as well as the mosaic distribution of mutant mtDNAs in each cell or tissue does not support the hypothesis that mtDNA somatic mutations are per se the cause of the observed agerelated OXPHOS decline. 20 Indeed, the direct causal linkage between age-related tissue dysfunction and mtDNA mutant load is controversial. 21,22 The second rationale suggesting a possible central role of mtDNA in successful aging and longevity regards the complex cross-talk between mitochondrial genome and nuclear genome.…”

Section: Figurementioning

confidence: 99%

Inherited Variability of the Mitochondrial Genome and Successful Aging in Humans

Benedictis

Carrieri

Varcasia

et al. 2000

Annals of the New York Academy of Sciences

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Increasing data indicate that polymorphic variants of nuclear loci can affect rate and quality of aging in humans. However, the mitochondrial genome is another good candidate, because of the central role played by mitochondrial genes in oxidative phosphorylation (OXPHOS) and cell metabolism. A characteristic of the mitochondrial genome (mtDNA) is the high level of interindividual variability that ensues from high mutation rate and unilinear inheritance. Related groups of germline/inherited mtDNA polymorphisms (haplogroups) have been identified as continent‐specific sets of stable/ancient/associated restriction fragment length polymorphisms in the mtDNA coding region, representing markers capable of exactly depicting the mtDNA pool of a specific population. The hypothesis can be put forward that mtDNA variants included in a haplogroup may have similar OXPHOS efficiency and therefore act as genetic factors predisposing to individual successful or unsuccessful aging. This idea can be explored by sampling groups of individuals of different ages from a well‐defined population and comparing the pools of mtDNA haplogroups between samples. The results obtained by screening mtDNA haplogroups in about 800 Italians of different ages, including more that 200 centenarians, agree with the hypothesis that the inherited variability of the mitochondrial genome is associated with the chance of successful aging and longevity in humans.

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Section: Figurementioning

confidence: 99%

Inherited Variability of the Mitochondrial Genome and Successful Aging in Humans

Benedictis

Carrieri

Varcasia

et al. 2000

Annals of the New York Academy of Sciences

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“…1 It was first recognized that somatic mutations accumulate during aging, 2 suggesting that dysfunction of mtDNA, which is essential in the energy balance of the cell, but which also is responsible for most of the endogenous free radicals and for apoptosis regulation, may play a role in the pathophysiology of aging and senescence. 3 On the other hand, increasing evidences indicate that mtDNA inherited variability plays a role in successful aging and longevity. 4 ± 7 Recently it was observed that in Italy the population pool of mtDNA haplogroups is different between healthy centenarians and young individuals, the main difference being sustained by the J haplogroup whose frequency increased from 2% in controls to about 20% in male centenarians.…”

Section: Introductionmentioning

confidence: 99%

Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians

et al. 2001

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Previous studies have shown that mitochondrial DNA (mtDNA) haplogroup J is significantly over-represented in healthy centenarians with respect to younger controls, thus suggesting that this haplogroup predisposes to successful aging and longevity. On the other hand, the same haplogroup is reported to have elevated frequency in some complex diseases. To verify if centenarians clustered in a particular lineage within J we have sequenced the D-loop region from 18 centenarians and 18 younger controls, previously characterized to be J. Then the entire mtDNA molecule was sequenced in a sub-sample of nine centenarians to find possible functional mutations associated with haplogroup J in successful aging. No clustering of the J haplogroup mtDNA from centenarians was observed. In addition, most of the mutations found are known as diseaseassociated mutations. The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait. European Journal of Human Genetics (2001) 9, 701 ± 707.

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Increased expression of mitochondrial transcription factor A and nuclear respiratory factor‐1 in skeletal muscle from aged human subjects

et al. 2001

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The expression of two factors involved in the nuclearm itochondrial crosstalk, namely the mitochondrial transcription factor A (TFAM) and the nuclear respiratory factor-1 (NRF-1), was studied in human skeletal muscle biopsies of young and aged subjects. Aged subjects presented a 2.6-fold and an 11-fold increase of the levels of TFAM protein and TFAM mRNA, respectively. The increased expression of TFAM was associated to the doubling of NRF-1 DNA-binding affinity and to a 6-fold increase of NRF-1 mRNA level. The upregulation of TFAM and NRF-1, in aged skeletal muscle, appears involved in the pathway leading to the age-related increase of mitochondrial DNA content. ß

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Age-Linked Changes in the Genotype and Phenotype of Mitochondria

Cited by 5 publications

References 136 publications

Inherited Variability of the Mitochondrial Genome and Successful Aging in Humans

Inherited Variability of the Mitochondrial Genome and Successful Aging in Humans

Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians

Increased expression of mitochondrial transcription factor A and nuclear respiratory factor‐1 in skeletal muscle from aged human subjects

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