مقاله انگلیسی رایگان در مورد تغییر فعالیت میتوکندری و موقعیت ردوکس در اووسیت و زیگوت با چاقی ناشی از رژیم غذایی مادر

The negative impact of obesity on reproductive success is well documented but the stages at which development of the conceptus is compromised and the mechanisms responsible for the developmental failure still remain unclear. Recent findings suggest that mitochondria may be a contributing factor. However to date no studies have directly addressed the consequences of maternal obesity on mitochondria in early embryogenesis. Using an established murine model of maternal diet induced obesity and a live cell dynamic fluorescence imaging techniques coupled with molecular biology we have investigated the underlying mechanisms of obesity-induced reduced fertility. Our study is the first to show that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and zygotes. Specifically, maternal diet-induced obesity in mice led to an increase in mitochondrial potential, mitochondrial DNA content and biogenesis. Generation of reactive oxygen species (ROS) was raised while glutathione was depleted and the redox state became more oxidised, suggestive of oxidative stress. These altered mitochondrial properties were associated with significant developmental impairment as shown by the increased number of obese mothers who failed to support blastocyst formation compared to lean dams. We propose that compromised oocyte and early embryo mitochondrial metabolism, resulting from excessive nutrient exposure prior to and during conception, may underlie poor reproductive outcomes frequently reported in obese women.

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Obesity and related metabolic disorders are a major health issue worldwide. With increasing prevalence in all populations and age groups, the proportion of women of reproductive age who are obese is rising [1]. Evidence is growing that excessive body fat has a detrimental effect on female fertility and pregnancy [2]. Obese women take longer to conceive and have a higher risk of miscarriage compared to lean women [3].Obesity also impairs the immediate outcome of assisted reproductive technologies suggesting that maternal body mass index (BMI) may influence the potential for fertilisation and viability of early embryos [4]. Since the earliest stages of embryo development are primarily controlled by the oocyte, it is likely that a sub-optimal environment within the ovary and/or oviduct accounts for these poor reproductive outcomes.

As recently reviewed [5], understanding of the effects of maternal obesity on the structure and metabolism in oocytes and pre-implantation embryos is very limited. It has been proposed that a high plane of nutrition might lead to excessive enrichment of the reproductive milieu [6]. This in turn may induce alterations in oocyte metabolism and impede embryonic development. Indeed several studies have shown that abnormally high or low rates of metabolism may compromise oocyte and embryo development [7,8]. Mitochondria are likely candidates for compromised metabolism in the embryo; these organelles are exclusively maternal in origin, and thus a deleterious influence of maternal BMI on mitochondria in the oocyte would strongly influence embryonic metabolism. Mitochondria also perform numerous regulatory functions during oocyte maturation [9], fertilization, initiation and progression of preimplantation embryos [10]. As energy producer, the central and most important function of mitochondria is the synthesis of adenosine triphosphate (ATP) by oxidative phosphorylation, a mechanism coupling the oxidation of nutrients and reducing equivalents (NAD(P)H, FADH2) with the phosphorylation of adenosine diphosphate. Both cytosolic and mitochondrial sources of NAD(P)H along with mitochondrial FADH2 stimulate the mitochondrial electron transport chain to pump H out of the mitochondrial matrix thereby hyperpolarising the inner mitochondrial membrane and generating the protonmotive force used to generate ATP. Electron donors NAD(P)H and FADH2 besides being used for energy production set the intracellular redox state. NADH oxidation in the mitochondria will produce ROS whereas NADPH oxidation (in the cytosol and mitochondria) serves to rejuvenate the antioxidant defence by reducing peroxiredoxins, thioredoxin and oxidised glutathione.