Carmen Díez-Sánchez

Human mtDNA Haplogroups Associated with High or Reduced Spermatozoa Motility

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.

Human mitochondrial haplogroup H: the highest VO2max consumer--is it a paradox?

Mitochondrial background has been demonstrated to influence maximal oxygen uptake (VO(2max), in mLkg(-1)min(-1)), but this genetic influence can be compensated for by regular exercise. A positive correlation among electron transport chain (ETC) coupling, ATP and reactive oxygen species (ROS) production has been established, and mitochondrial variants have been reported to show differences in their ETC performance. In this study, we examined in detail the VO(2max) differences found among mitochondrial haplogroups. We recruited 81 healthy male Spanish Caucasian individuals and determined their mitochondrial haplogroup. Their VO(2max) was determined using incremental cycling exercise (ICE). VO(2max) was lower in J than in non-J haplogroup individuals (P=0.04). The H haplogroup was responsible for this difference (VO(2max); J vs. H; P=0.008) and this group also had significantly higher mitochondrial oxidative damage (mtOD) than the J haplogroup (P=0.04). In agreement with these results, VO(2max) and mtOD were positively correlated (P=0.01). Given that ROS production is the major contributor to mtOD and consumes four times more oxygen per electron than the ETC, our results strongly suggest that ROS production is responsible for the higher VO(2max) found in the H variant. These findings not only contribute to a better understanding of the mechanisms underneath VO(2max), but also help to explain some reported associations between mitochondrial haplogroups and mtOD with longevity, sperm motility, premature aging and susceptibility to different pathologies.

Mitochondrial DNA Content of Human Spermatozoa

Abstract Sperm mitochondria play an important role in spermatozoa because of the high ATP demand of these cells. Different mitochondrial DNA (mtDNA) mutations and haplogroups influence sperm function. The mtDNA dose also contributes to genetic variability and pathology in different tissues and organs, but nothing is known about its relevance in the performance of spermatozoa. We estimated the variability in mtDNA content within a population of men. Different mtDNA:nuclear DNA ratios were characteristic of progressive and nonprogressive spermatozoa, confirming the influence of mtDNA content on sperm functionality. We also estimated that the absolute content of mtDNA was 700 and 1200 mtDNA copies per cell in progressive and nonprogressive human spermatozoa, respectively. These results suggest that a marked increase of mtDNA copy number per cell volume takes place during spermatogenesis.

The role of the mitochondrion in sperm function: is there a place for oxidative phosphorylation or is this a purely glycolytic process?

We review here the current knowledge related to the metabolic pathways used by spermatozoa to meet their high demands for ATP. This is discussed with special emphasis on one of their key roles, motility. We believe that the controversy among glycolytic and oxidative phosphorylation supporters is artificial and, as it happens in many other cell types, the source of ATP is multiple and depends on external inputs.

Human mitochondrial variants influence on oxygen consumption

This work investigates if human mitochondrial variants influence on maximal oxygen consumption (VO(2max)). With this purpose we recruited, as a uniform population in term of nutritional habits and life style, 114 healthy male Spanish subjects that practiced fitness exercises 3-4 times a week. Once mtDNA haplogroups were determined, we found that J presents with lower VO(2max) (P=0.02) than nonJ variants. J has been related with a lower efficiency of electron transport chain (ETC), diminished ATP and ROS production. Thus, the difficult to compensate the mitochondrial energetic deficiency could explain the accumulation of J haplogroup in LHON and multiple sclerosis. Furthermore, the lower ROS production associated to J could also account for the accrual of this variant in elderly people consequent to a decreased oxidative damage.

20 years of human mtDNA pathologic point mutations: carefully reading the pathogenicity criteria.

Despite the strong purifying selection that occurs during embryonic development, the particular location and features of mitochondrial DNA make it especially susceptible to accumulating point mutations, giving rise to a large number of mitochondrial DNA variants. Many of these will have moderate or no phenotypic effects but others will be the cause of very dramatic diseases, usually known as mitochondriopathies. Because of the abundance of different mitochondrial DNA variants, it is not easy to determine whether a new mutation is pathogenic. To facilitate this task, different criteria have been proposed, but they are often either too severely or too loosely applied. Citing examples from the literature, in this paper we discuss some critical aspects of these criteria.

Mitochondria from ejaculated human spermatozoa do not synthesize proteins

Sperm motility is dependent on mitochondrial ATP production that relies on the coordinated expression of the mitochondrial and nuclear genomes. It is generally accepted that mammalian ejaculated spermatozoa retain the ability to synthesize mtDNA‐encoded proteins but not most of the nuclear ones. This implies an asynchronous regulation of the oxidative phosphorylation‐related genes encoded by each genome. Trying to investigate this issue, we unexpectedly found that ejaculated human spermatozoa do not synthesize mtDNA‐encoded proteins. Moreover, we estimated that the discrepancy between our observations and those published elsewhere was due to a chloramphenicol‐sensitive protein synthesis attributed to mitochondria that instead corresponds to contaminating bacteria.

Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H.

It has been suggested that human mitochondrial variants influence maximal oxygen uptake (VO2max). Whether mitochondrial respiratory capacity per mitochondrion (intrinsic activity) in human skeletal muscle is affected by differences in mitochondrial variants is not known. We recruited 54 males and determined their mitochondrial haplogroup, mitochondrial oxidative phosphorylation capacity (OXPHOS), mitochondrial content (citrate synthase (CS)) and VO2max. Intrinsic mitochondrial function is calculated as mitochondrial OXPHOS capacity divided by mitochondrial content (CS). Haplogroup H showed a 30% higher intrinsic mitochondrial function compared with the other haplo group U. There was no relationship between haplogroups and VO2max. In skeletal muscle from men with mitochondrial haplogroup H, an increased intrinsic mitochondrial function is present.

Steady exercise removes VO2max difference between mitochondrial genomic variants

It has been clearly established that mitochondrial variants, among other potential factors, influence on VO(2max). With this study we sought to determine whether this genetic predisposition could be modified by steady exercise. Mitochondrial genetic variants were determined in 70 healthy controls (CON) and in 77 athletes who trained regularly (50 cyclists, aerobic training (AER), and 27 runners of 400m, anaerobic training (NoAER)). All of them were male Spanish Caucasian individuals. A maximum graded exercise test (GXT) in cycle-ergometer was performed to determine VO(2max) (mL kg(-1)min(-1)). Our results confirmed that, in CON, VO(2max) (P=0.007) was higher in Non-J than J individuals. Furthermore, we found that AER and NoAER showed, as it could be expected, higher VO(2max) than CON, but not differences between mitochondrial variants have been found. According with these findings, the influence of mitochondrial DNA (mtDNA) variants on VO(2max) has been confirmed, and a new conclusion has arisen: the steady exercise is able to remove this influence. The interest of these promising findings in muscular performance should be further explored, in particular, the understanding of potential applications in sport training and in muscle pathological syndromes.

Effect of endurance and resistance training on regional fat mass and lipid profile

The purpose of this study was to investigate the effect of 10-week of endurance training or resistance training on regional and abdominal fat, and in the lipid profile, examining the associations among the changes in body composition, weight, waist circumference and lipid profile. Body composition, waist circumference and lipid profile were analyzed in 26 volunteers healthy young men (age 22.5 ± 1.9 yr), randomly assigned to: endurance group (EG), resistance group (RG) or control group (CG). The EG significantly decreased after training the body weight, body mass index, total body fat and percentage of fat, fat and percentage of fat at the trunk and at the abdominal region and High-Density Lipoprotein. The RG significantly increased total lean mass and decreased total cholesterol, High-Density and Low- Density Lipoprotein. Close relationship were found among changes in weight, total lean mass, regional fat mass, waist circumference and changes in lipid profile (all p < 0.05). We concluded that 10-week of endurance training decreased abdominal and body fat in young men, while 10-week of resistance training increased total lean mass. These types of training had also effects on lipid profile that seem to be to some extent associated to changes in body composition; however it requires additional investigation.