Large Scale 7436-bp Deletions in Human Sperm Mitochondrial DNA with Spermatozoa Dysfunction and Male Infertility

Abstract

IntrOductIOnSperm motility is essential factor of fertile men. During fertilization, sperm cells require large amount of energy for their movement of flagella and active functioning. Nearly, 100 mitochondria are present in the midpiece of every mature human spermatozoon to provide energy quickly and effectively for sperm motility [1]. The oxidative phosphorylation of mitochondria generates energy in the form of ATP for flagellar movement of spermatozoa. In mitochondria, Reactive Oxygen Species (ROS) is generated during oxidative phosphorylation and increase the risk of Mitochondrial (mtDNA) damage [2]. The oxidative phosphorylation comprises a series of protein complexes that are encoded by both nuclear genes and mitochondrial genes [3]. Mitochondria contain their own genomic DNA and express independently in matrix of mitochondria. It contains 16569 base pairs that are categorised in 13 genes of respiratory chain complex subunits, along with the 22 tRNAs and 2 rRNAs (12S and 16S) involved in protein synthesis [4]. The mtDNA replicates rapidly by D-loop mechanism without proof-reading and DNA repair mechanisms. So, it enhances mutation rate 10-100 times higher than that of nuclear DNA [5]. Furthermore, sperm cells are susceptible to damage from oxidants because they lack endogenous antioxidants activity and mtDNA is attached to the mitochondrial inner membrane where ROS are continuously generated as byproducts of electron ABStrActIntroduction: Mitochondria and mitochondrial DNA are essential to sperm motility and fertility. It controls growth, development and differentiation through oxidation energy supply. Mitochondrial (mtDNA) deletions or mutation are frequently attributed to defects of sperm motility and finally these deletions lead to sperm dysfunction and causes infertility in male.

Comparison of large‐scale deletions of the sperm mitochondrial DNA in normozoospermic and asthenoteratozoospermic men

“…They indicated that 7436‐bp deletion of mtDNA is associated with abnormal sperm motility, so, the nonmotile spermatozoa in 40% percoll fractions showed more mtDNA deletions (7.2%) than the motile spermatozoa in 80% percoll fraction (2.7%). Other studies, in consistence with our results, confirmed the association of large‐scale 7436‐bp sperm mtDNA deletions with poor sperm motility in asthenozoospermia and OAT patients, but the frequencies of 7436‐bp deletions are less than that of 4977‐bp “common” deletions . In IVF/intracytoplasmic sperm injection (ICSI) cases, spermatozoa with a significant load of “common” mtDNA 4977‐bp deletion do not produce enough energy for their movement and thus reduce male fertility, mainly affecting oocyte fertilization .…”

“…In general, the frequency of 7436‐bp deletions in sperm mtDNA was the lowest than two other deletions (4.8 and 4.9 Kb) in both infertile and control groups. Interestingly, Ambulkar et al and Rani et al could not find deletion of 7436 bp in normospermic subjects. St. John et al showed the persistence of multiple mtDNA deletions in both normozoospermic and oligoasthenoteratozoospermic (OAT) men.…”

“…Ambulkar et al, reported that 20.5% asthenozoospermia (8/39) and 28.6% OAT (6/21) had more number of mtDNA 4977‐bp deletions than normal sperm, and this deletion was more common in 40% (23.3%) fraction than 60% (11.6%) and 80% (5%) fractions in percoll gradient. In another study, Ambulkar et al also revealed that 8.57% (6/70) asthenozoospermia and 5% (2/40) OAT patients and overall 7.2% (8/110) patients had showed 7436‐bp sperm mtDNA deletions in infertile men, but there were no such deletions in fertile normozoospermic subjects. They indicated that 7436‐bp deletion of mtDNA is associated with abnormal sperm motility, so, the nonmotile spermatozoa in 40% percoll fractions showed more mtDNA deletions (7.2%) than the motile spermatozoa in 80% percoll fraction (2.7%).…”

“…The large-scale deletions of 4977-bp have been known as "common" deletions and mtDNA damage indicators that have been associated with a number of pathological phenotypes in mitochondrial disorder 8,17,20,21 and aging in various human tissues. 14 Several studies have also demonstrated the association between the "common" 4977-bp deletion and other large-scale deletions with human sperm dysfunction, [22][23][24][25][26][27][28][29][30] but they have produced contradictory results. Overall, they suggested that these deletions cause infertility in men by affecting sperm motility.…”

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

“…Interestingly, mtDNA 4977 has been recorded in the spermatozoa of infertile males with asthenozoospermia and oligoasthenozoospermia [148,149]. An alternative large-scale mtDNA deletion comprising 7436 bp (mtDNA 7436 ) has also been reported in low-motility human spermatozoa [150]. In addition to the genes excised by mtDNA 4977 , mtDNA 7436 also eliminates genes encoding subunit 6 of Complex I (ND6) and cytochrome b from the mtDNA genome (see Figure 3).…”