Polygenic expression of teratozoospermia and normal fertility in B10.MOL‐TEN1 mouse strain

Subfertility and infertility are two major reproductive health problems in human and domestic animals. The contribution of the genotype to these conditions is poorly understood. To examine the genetic basis of male subfertility, we analyzed its relationship to sperm morphology in B10.MOL‐TEN1 mice, which shows high‐frequencies (about 50%) of morphologically abnormal sperm. Drastic histological changes were also found in the testis of the B10.MOL‐TEN1. Segregation analysis showed that the abnormal sperm phenotype in B10.MOL‐TEN1 was inherited and was predictably controlled by at least three loci. We also found that male fertility of this strain was normal. These findings indicate a complicated relationship between sperm morphology and male subfertility.     

A mitochondrial superoxide theory for oxidative stress diseases and aging

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O₂^•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q₁₀) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.     

Insulin suppresses IKs (KCNQ1/KCNE1) currents,which require β-subunit KCNE1

Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia. In an animal model of type 1 diabetes mellitus, several ion currents, including the slowly activating delayed rectifier potassium current (I_Ks), are altered. The I_Ks channel is composed of KCNQ1 and KCNE1 subunits, whose genetic mutations are well known to cause long QT syndrome. Although insulin is known to affect many physiological and pathophysiological events in the heart, acute effects of insulin on cardiac ion channels are poorly understood at present. This study was designed to investigate direct electrophysiological effects of insulin on I_Ks (KCNQ1/KCNE1) currents. KCNQ1 and KCNE1 were co-expressed in Xenopus oocytes, and whole cell currents were measured by a two-microelectrode voltage-clamp method. Acute application of insulin suppressed the KCNQ1/KCNE1 currents and phosphorylated Akt and extracellular signal-regulated kinase (ERK), the two major downstream effectors, in a concentration-dependent manner. Wortmannin (10^?6 M), a phosphoinositide 3-kinase (PI3K) inhibitor, attenuated the suppression of the currents and phosphorylation of Akt by insulin, whereas U0126 (10^?5 M), a mitogen-activated protein kinase kinase (MEK) inhibitor, had no effect on insulin-induced suppression of the currents. In addition, insulin had little effect on KCNQ1 currents without KCNE1, which indicated an essential role of KCNE1 in the acute suppressive effects of insulin. Mutagenesis studies revealed amino acid residues 111–118 within the distal third C-terminus of KCNE1 as an important region. Insulin has direct electrophysiological effects on I_Ks currents, which may affect cardiac excitability.