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Rel 3.0 - 9th February 1998



Mitochondrial dysfunction in the senescence accelerated mouse.

Free Radic Biol Med 1998 Jan 1;24(1):85-92

Nakahara H, Kanno T, Inai Y, Utsumi K, Hiramatsu M, Mori A, Packer L

Institute of Medical Science, Center for Adult Diseases, Kuraashiki, Japan.

Oxidative damage to DNA, proteins, and lipids in mitochondria caused by free radicals may be one factor in aging. Oxidative phosphorylation was estimated in liver mitochondria from senescence accelerated mice (SAMP8) and a senescence resistant substrain (SAMR1). The respiratory control ratio decreased in liver mitochondria of SAMP8 during aging, and it was estimated that at 18 months of age this respiratory control value suggested that it might be insufficient to provide ATP synthesis necessary for normal cell metabolism. In addition, the ADP/O, an index of efficiency of ATP synthesis, was depressed at 18 months of age. Dinitrophenol-dependent uncoupled respiration in liver mitochondria of SAMP8 mice was markedly decreased with aging, suggesting a dysfunctional energy transfer mechanism in mitochondria of aged SAMP8 mice. Active uptake of calcium in liver mitochondria was markedly dysfunctional in SAMP8 mice with aging, and uncoupling of respiration was induced more easily in aged mitochondria. Milder effects on these functional parameters were observed in SAMR1 mice. A similar dysfunction was also observed in heart mitochondria of SAMP8 mice at 12 months of age. The amount of Bcl-x in liver mitochondria was slightly decreased in SAMP8. We suggest that these changes in mitochondrial function may be related to the shorter life span of the senescence accelerated mouse.

Replicative senescence of normal human oral keratinocytes is associated with the loss of telomerase activity without shortening of telomeres.

Cell Growth Differ 1998 Jan;9(1):85-95

Kang MK, Guo W, Park NH

Dental Research Institute, School of Dentistry, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles 90095-1668, USA.

Telomerase activity was analyzed in 7 different cultures of secondary normal human oral keratinocytes (NHOKs), 1 normal human oral epithelial tissue specimen, 1 immortalized human oral keratinocyte (HOK) cell line, and 10 human oral cancer cell lines using the PCR-based telomeric repeat amplification protocol assay. Telomerase activity was found in all tested cells and tissue, but the activity in NHOKs and epithelial tissue was lower than that in other tested cell lines. Inasmuch as continued subculture of NHOKs results in replicative senescence, we investigated the association between telomerase activity and replicative senescence by evaluating the enzyme activity in NHOK cultures with different population doubling levels. Three different NHOK cultures were independently subcultured until these cells reached the postmitotic stage. Unlike in fibroblasts derived from the human oral cavity, significant telomerase activity was detected in rapidly proliferating NHOKs, and telomerase activity was barely detectable in the keratinocytes near and at senescence. However, the terminal restriction fragment consisting of telomeric DNA was found to be constantly maintained at approximately 6.0 kilobases in NHOKs without any detectable shortening of telomeres by subcultures. Intracellular p53 and p21WAF1/CIP1 protein levels in NHOKs were gradually and significantly diminished by the passage of cells. These data indicate that actively proliferating NHOKs contain telomerase activity and that replicative senescence of NHOKs is associated with the loss of telomerase activity without shortening of telomeres. However, replicative senescence of NHOKs is apparently not linked to an accumulation of wild-type p53 and/or p21WAF1/CIP1 proteins in these cells.

Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process.

Biochem Mol Med 1997 Dec;62(2):165-171

Barrientos A, Casademont J, Cardellach F, Ardite E, Estivill X, Urbano-Marquez A, Fernandez-Checa JC, Nunes V

Department of Internal Medicine, Hospital Clinic, University of Barcelona, Spain.

It has been widely postulated that age-dependent changes in the mitochondrial genetic system may contribute to the human aging process. We recently reported unchanged specific activities of mitochondrial respiratory chain enzymes and a decrease in oxidation capacity of different substrates with aging, due, in part, to some confounding variables such as physical activity or tobacco consumption. The present study deals with age-related changes in muscle mtDNA structure and its biogenesis in humans. We found a low prevalence of mtDNA rearrangements with aging, only detected by PCR. The mtDNA content increased significantly with age (b = 0.0115, P < 0.0001). Also, an unchanged steady-state level of mitochondrial transcripts, a reduced transcription rate (P < 0.0001), and an increase in mitochondrial membrane lipid peroxidation (P < 0.0001) were observed in aging. These data demonstrate that minor structural mtDNA changes appear during the human aging process. By contrast, alterations in mitochondrial homeostasis ultimately producing modifications in mitochondrial biogenesis rates could play a role in the process of human senescence.

Plasmodium falciparum telomerase: de novo telomere addition to telomeric and nontelomeric sequences and role in chromosome healing.

Mol Cell Biol 1998 Feb;18(2):919-925

Bottius E, Bakhsis N, Scherf A

Unite de Parasitologie Experimentale, CNRS URA 1960, Institut Pasteur, Paris, France.

Telomerase, a specialized cellular reverse transcriptase, compensates for chromosome shortening during the proliferation of most eucaryotic cells and contributes to cellular immortalization. The mechanism used by the single-celled protozoan malaria parasite Plasmodium falciparum to complete the replication of its linear chromosomes is currently unknown. In this study, telomerase activity has for the first time been identified in cell extracts of P. falciparum. The de novo synthesis of highly variable telomere repeats to the 3' end of DNA oligonucleotide primers by plasmodial telomerase is demonstrated. Permutated telomeric DNA primers are extended by the addition of the next correct base. In addition to elongating preexisting telomere sequences, P. falciparum telomerase can also add telomere repeats onto nontelomeric 3' ends. The sequence GGGTT was the predominant initial DNA sequence added to the nontelomeric 3' ends in vitro. Poly(C) at the 3' end of the oligonucleotide significantly alters the precision of the new telomerase added repeats. The efficiency of nontelomeric primer elongation was dependent on the presence of a G-rich cassette upstream of the 3' terminus. Oligonucleotide primers based on natural P. falciparum chromosome breakpoints are efficiently used as telomerase substrates. These results imply that P. falciparum telomerase contributes to chromosome maintenance and to de novo telomere formation on broken chromosomes. Reverse transcriptase inhibitors such as dideoxy GTP efficiently inhibit P. falciparum telomerase activity in vitro. These data point to malaria telomerase as a new target for the development of drugs that could induce parasite cell senescence.



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