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, 67 (3), 682-96

Human mtDNA Haplogroups Associated With High or Reduced Spermatozoa Motility


Human mtDNA Haplogroups Associated With High or Reduced Spermatozoa Motility

E Ruiz-Pesini et al. Am J Hum Genet.


A variety of mtDNA mutations responsible for human diseases have been associated with molecular defects in the OXPHOS system. It has been proposed that mtDNA genetic alterations can also be responsible for sperm dysfunction. In addition, it was suggested that if sperm dysfunction is the main phenotypic consequence, these mutations could be fixed as stable mtDNA variants, because mtDNA is maternally inherited. To test this possibility, we have performed an extensive analysis of the distribution of mtDNA haplogroups in white men having fertility problems. We have found that asthenozoospermia, but not oligozoospermia, is associated with mtDNA haplogroups in whites. Thus, haplogroups H and T are significantly more abundant in nonasthenozoospermic and asthenozoospermic populations, respectively, and show significant differences in their OXPHOS performance.


Figure  1
Figure 1
Dependence of the sperm flagella movement on the activity of the mitochondrial oxidative phosphorylation complexes. The activity of several mitochondrial OXPHOS complexes was inhibited by increasing concentrations of the indicated drug, and the proportion of sperm cells able to move following a quick and straight trajectory (open circles) or that manifest any kind of flagella activity (close circles) was evaluated after 3 min in the presence of the drug by microscopy count in a Neubauer chamber. Data represent average ± standard error of the mean (SEM) of four independent experiments.
Figure  2
Figure 2
Vertical-progression analysis. Differences in the ability of spermatozoa carrying different mtDNAs to swim from the semen into a capillar tube in a period of 30 min. n is the number of samples, and the asterisk (*) indicates significant differences between the distance of vertical progression for haplogroup T versus haplogroup H carrying mtDNA samples (P=.029; Fisher’s PLSD test).
Figure  3
Figure 3
Sequence analysis of mtDNA haplogroup T carriers. Nucleotide differences at the hypervariable region I (HVRI) of the noncoding region of mtDNA that define 20 haplotypes in 29 individuals harboring the T haplogroup. The phenotype of the different individuals is indicated as SAP (blackened circles) or non-AP (unblackened circles); all the other samples showed MAP (striped circles). Each individual is indicated by a letter/number code.
Figure  4
Figure 4
OXPHOS-activity analysis. Bar diagrams showing the differences in activity of two fully nuclear-encoded mitochondrial enzymes, citrate synthase (CS, a mitochondrial-matrix enzyme) and succinate dehydrogenase (complex II) and two enzymatic complexes partially encoded by mtDNA: NADH dehydrogenase (complex I) and cytochrome c oxidase (COX or complex IV). Bars represent specific enzyme activity (mean ± SEM) for the different haplogroups when either all (gray) or only MAP (crossed) individuals were considered. ANOVA test indicate the absence of significant differences between haplogroups for CS, complex II, and complex I, as well as a significant difference for COX activity when all (P=.0031) or only MAP (P=.0464) individuals were considered. Post hoc analysis by Fisher’s PLSD test reveals that T and Rest showed a significantly lower COX activity when compared with H, regardless of whether all or only MAP individuals were considered (P<.05).
Figure  5
Figure 5
Bar diagrams showing the relative activity of three respiratory complexes (complexes I and IV, partially encoded by mtDNA, and complex II, fully encoded by nuclear genes) in each haplogroup, when they are normalized by the activity of citrate synthase. Data are given as mean ± SEM in arbitrary units.
Figure  6
Figure 6
Haplogroup T–specific tRNA mutations. Sequencing of all the tRNA genes of one individual showed, in two tRNAs, mutations that were specific for the haplogroup T individuals: left, A15928G transition at the top of anticodon stem of the tRNA Thr; right, U10463C transition at the bottom of the acceptor stem of the tRNA Arg.

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