Search

Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson’s chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95%CI: 1.020–2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95%CI: 1.250–5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor. [ABSTRACT FROM AUTHOR]

Mitochondria are the energy metabolism centers of the cell. More than 95% of cellular energy is produced by mitochondrial oxidative phosphorylation. Hypoxia affects a wide range of energy generation and consumption processes in animals. The most important mechanisms limiting ATP consumption increase the efficiency of ATP production and accommodate the reduced production of ATP by the body. All of these mechanisms relate to changes in mitochondrial function. Mitochondrial function can be affected by variations in mitochondrial DNA, including polymorphisms, content changes, and deletions. These variations play an important role in acclimatization or adaptation to hypoxia. In this paper, the association between mitochondrial genome sequences and high-altitude adaptation is reviewed. [ABSTRACT FROM AUTHOR]

Background.—: The role of genetics in determining an individual''s susceptibility to high altitude pulmonary edema (HAPE) is unclear. However a number of genetic polymorphisms have recently been found to be overrepresented in patients with HAPE. Changes at the mitochondrial level may play an important role in the human body''s adaptation to hypoxia. Polymorphisms of mitochondrial DNA (mtDNA) have been shown to be responsible for differences in organelle function. Therefore, the frequency of mtDNA 3397A/G and 3552T/A polymorphisms were studied to determine their potential role in HAPE. Objectives.—: To further study the role of mtDNA 3397A/G and 3552T/A variations of reduced nicotinamide adenosine dinucleotide dehydrogenase 1 in HAPE susceptibility. Methods.—: The single-nucleotide polymorphisms of mtDNA 3397 and 3552 in patients with HAPE (n = 132) and their matched control subjects (n = 233) were studied using polymerase chain reaction sequencing. Results.—: The frequency of mtDNA 3397G in the HAPE group (2.3%) was significantly higher than that of the control group (0%; P = .021; odds ratio, 2.806; 95% confidence interval, 2.443 to 3.223). The frequency of mtDNA 3552A in the HAPE group (6.8%) also was significantly higher than in the control group (1.7%; P = .012; odds ratio, 4.198; 95% confidence interval, 1.264 to 13.880). Conclusions.—: In this study, we present the first evidence of differences in mtDNA polymorphism frequencies between HAPE victims and healthy Han Chinese. Genotypes of mtDNA 3397G and 3552A were correlated with HAPE susceptibility. This result could contribute to defining the role of the mitochondrial genome in the pathogenesis of HAPE. [Copyright &y& Elsevier]

Tibetans are well adapted to living and thriving in high-altitude environments. Mitochondria are central links to oxygen consumption, and variations in mitochondrial DNA (mtDNA) could play a role in high-altitude adaptation. Alleles at several polymorphic sites in mtDNA define common haplotypes, or haplogroups, including some that have been implicated in the risk of developing certain diseases. However, few reports have determined whether relationships exist between haplogroups and high-altitude adaptation in the Tibetan population. The D4 haplogroup is a major haplogroup of the Han Chinese. In the present study, genotypes of 12 polymorphisms were determined in members of a Tibetan population ( n == 72), low altitude-Han (la-Han, n == 144), and high altitude-Han (ha-Han, n == 227) populations using polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-ligase detection reaction assays. The mitochondrial haplogroup D4 was negatively associated with high-altitude adaptation in Tibetans ( P == 0.001 vs. la-Han, OR == 0.166, 95% CI == 0.048-0.567; P == 0.009 vs. ha-Han OR == 0.232, 95% CI == 0.069-0.778). The frequency of the nt3010G-nt3970C haplotype was significantly higher in Tibetans than in la-Han ( P == 0.000) and ha-Han ( P == 0.001) subjects. Findings in the present study suggest that unique mitochondrial variations determine a genetic background that is associated with high-altitude adaptation in the Tibetan population. [ABSTRACT FROM AUTHOR]

Objective: Mitochondria are factories for energy production and genetic alterations in mtDNA will directly impact OXPHOS function. The copy number of mtDNA (i.e., the number of mtDNA per spermatozoon) is one of the major mitochondrial genetic features. Besides mtDNA copy number, the change of either mtDNA or nDNA integrity is another important factor causing asthenospermia, or poor sperm motility in infertile men. In this study, we investigated the mtDNA copy number and the integrities of mtDNA and nDNA respectively in semen samples from different donors at 5,300 m altitudes. Methods: Total DNA was extracted from semen samples from donors in two different altitudes. Quantitative PCR was performed to evaluate the mtDNA copy number. PCR amplification was used to examine the integrity of sperm mtDNA. Flow cytometry was carried out to investigate sperm nDNA integrity. All data were analyzed to show the statistical significance. Results: Sperm mtDNA copy number for those living at high altitude (5,300 m) for one month was significantly higher ( P < 0.05) than for those at the lower altitude (1,400 m) or in donors who had been living at the 5,300 m altitude for 1 year. In addition, sperm mtDNA copy numbers were remarkably decreased ( P < 0.05) in those who had lived at the greater altitude for 1 year compared to those who had lived there for one month. The ratio of nDNA integrity among the 10,000 sperms at high altitude for one month was significantly lower ( P < 0.05) than that at the lower altitude (1,400 m) or at 5,300 m for 1 year, and the ratio of nDNA integrity sperms at high altitude for 1 year was increased, and higher than that for at the lower altitude ( P < 0.05). Conclusion: High altitude can alter the mtDNA copy number and nDNA integrity in the sperms. [ABSTRACT FROM AUTHOR]

Background: The identification of human mitochondrial DNA (mtDNA) sequence variations, especially single nucleotide polymorphisms (SNPs), is important for many applications. The PCR-ligase detection reaction (LDR) method can reduce false-positives and eliminate the need for both post-PCR and post-ligation purifications in SNP analyses. In addition, it has been successfully employed to detect point mutations in various nuclear genes. In this study, we used the PCR-LDR platform to characterize mtDNA SNPs. Methods: Multiplex PCR-LDRs were used to genotype 19 mtDNA single nucleotide polymorphic sites from 812 samples. Performance of the method was assessed by direct sequencing of 44 samples. Results: We established an overall 97.4% success rate with 99.2% accuracy using the multiplex PCR-LDR methodology. Conclusions: The PCR-LDR mtDNA genotyping technique is simple, highly accurate, has high-throughput, and is cost-effective. Therefore, this method is applicable to mtDNA haplotyping in various applications. Clin Chem Lab Med 2010;48:475–83. [ABSTRACT FROM AUTHOR]

Abstract: Pikas originated in Asia and are small lagomorphs native to cold climates. The plateau pika, Ochotona curzoniae is a keystone species on the Qinghai–Tibet Plateau and an ideal animal model for hypoxic adaptation studies. Altered mitochondrial function, especially cytochrome c oxidase activity, is an important factor in modulation of energy generation and expenditure during cold and hypoxia adaptation. In this study, we determined the complete nucleotide sequence of the O. curzoniae mitochondrial genome. The plateau pika mitochondrial DNA is 17,131bp long and encodes the complete set of 37 proteins typical for vertebrates. Phylogenetic analysis based on concatenated heavy-strand encoded protein-coding genes revealed that pikas are closer to rabbit and hare than to rat. This suggests that rabbit or hare would be a good control animal for pikas in cold and hypoxia adaptation studies. Fifteen novel mitochondrial DNA-encoded amino acid changes were identified in the pikas, including three in the subunits of cytochrome c oxidase. These amino acid substitutions potentially function in modulation of mitochondrial complexes and electron transport efficiency during cold and hypoxia adaptation. [Copyright &y& Elsevier]

The article discusses hypoxic pathophysiology and high-altitude medicine as of December 2012, with a focus on physiological adaptations in mitochondria and their potential role in high-altitude illness susceptibility. Topics include cerebral cortex mitochondria and the respiratory control rate (RCR), mitochondrial membrane potential (MMP), and genetic adaptations to hypobaric hypoxia exposure. Additional information is presented on the oxidative phosphorylation ratio (OPR) and Tibetans' mitochondrial DNA (mtDNA) sequences.