Interplay between oxidative stress, SIRT1, reproductive and metabolic functions

1Sirtuins (NAD dependant-deacylase) are involved in the deacetylation of histones and transcriptional factors regulating the cell cycle, resistance to oxidative stress, and metabolism. They are located in all essential parts of the cell, including the nucleus, cytoplasm, and mitochondria. SIRT1 has been called the “sensor” and “guardian of the redox state” in granulosa cells and oocytes(3). A vast range of cellular activities is controlled by SIRT1, including programmed cell death, autophagy, cell migration, and differentiation. This review aims to gather information about crosstalk between SIRT1 and OS, reproductive and metabolic functions (Table 1, Fig. 1).

2Sirtuins have been found to affect the reproductive physiology of females by acting as antioxidants against the ROS. They act as sensors and protectors of the redox environment within the ovarian granulosa cells. SIRT1, expressed at small concentrations in oocytes, is a chief participant during oogenesis that extends to metaphase II (MII). SIRT2, chiefly located in the cytoplasm, transitorily migrates to the nucleus to control chromatin condensation and regulate the cell cycle. SIRT3 functions during fertilization and the primary embryonic growth by participating in energy metabolism. SIRT5 prevents the cell from oxidative damage by activating the enzymes which are NADPH-producing. SIRT6 is associated with telomere stability; however, SIRT7 co-activates ribosomal DNA transcription.

3SIRT1 is also known to repair cells that have been damaged due to OS, thus preventing dysfunction of ovarian cells; it does this by deacetylation of members of the forkhead-box transcription factors (FOXO) family. SIRT1 also promotes mitochondrial biogenesis by activating the peroxisome proliferator-activated receptor co-activator PGC1-α in the presence of NAD. SIRT1 utilizes visfatin for accomplishing its effect against the oxidants. Visfatin is known to be an essential element in regulating the oxidative environment of the oocytes. However, SIRT1 is also responsible for regulating the function and expression of MnSOD.

4A recent study stated that Proopiomelanocortin (POMC) neuron specific ablation of SIRT1 did not change POMC, Adrenocorticotropic hormone (ACTH), and alpha-melanocyte-stimulating hormone (αMSH) levels. The pro-CRH is acted upon by prohormone convertases 1 and 2 (PC1 and PC2) post-translationally. In the Para Ventricular Nuclei (PVN), SIRT1 elevates the PC2 levels, which in turn increases the concentration of active CRH, stimulating the HPA axis. There is a probability that SIRT1 indirectly controls the HPA axis by regulating the PC1 and PC2 concentrations. Moreover, Resveratrol also augmented the expression and prolongation of the half-life of P450scc in the suprarenal gland, resulting in the increase of cortisol secretion from the adrenal cortical sites.

5Infertile couples are stressed because of the situation, and thus, their stress hormones are higher than normal. These disturbed hormones have an indirect effect on the HOP axis via OS, causing infertility. However, the cascade of high-stress hormones could be triggered by conditions other than infertility and can lead to subfertility. SIRT1 deficiency could be one reason.

6In particular, the role of different Sirtuins, particularly SIRT1 in reproduction, has been widely studied over the past decade. In the female reproductive system, SIRT1 regulates proliferation and apoptosis in granulosa cells (GCs), especially during the follicular atretic phase, and its down-regulation is associated with a reduced ovarian reserve. Porcine GCs transfected with SIRT1 showed increased proliferation markers proposing the role of SIRT1 in GC differentiation and luteinization. SIRT1 modulates the stress response to OS in GCs by targeting FOXL2, a transcription factor vital for ovarian functions and maintenance.

7It also delays postovulatory oocyte aging through its anti-oxidative actions and by improving mitochondrial function. SIRT1 is highly expressed in the hypothalamus, particularly in the GnRH neurons. Its role in the HPG axis has been identified in knockout mice, which had decreased GnRH expression and, in turn, decreased levels of both FSH and LH. Hypogonadotropic hypogonadism has also been reported in such mice due to GnRH neuronal migration.

8Increasing SIRT1 activity can improve fertility by conserving ovarian reserve, regulating proliferation and apoptosis of GCs, and protecting against OS. Sirtuin-mediated regulation of energy homeostasis, mitochondrial biogenesis, and chromatin remodeling can further be explored to identify its effectiveness in females with PCOS, diabetes, endometriosis, xenobiotic stress, and aging. Sirtuin-based signaling can, therefore, be applied as diagnostic tools and potential targets for therapeutic applications in reproductive medicine. Regulation of insulin sensitivity and maintenance of the energy balance via various pathways renders SIRT1 different from other family members.

9SIRT1 plays its role as an effective modulator in mammals’ oocytes at diverse phases of follicle maturation by modifying mitochondrial mechanisms to synthesize energy (13, 20). Within the oocytes, the mitochondrial enzymes (including MnSOD) are deacylated by SIRT1(21, 22).

10This has already been proven that SIRT1 demonstrates a front-line defense mechanism against the ROS through the FoxO3a-MnSod axis in the mouse’s immature ovarian oocytes at the germinal vesicle phase (GV).

11These conclusions validate SIRT1 as a principal and precise pharmacological focus against ROS destroying oocytes. They also propose SIRT1 to be a pharmacological excitation that might be an appropriate line to advance to treat improved oocyte achievement during OS-mediated physiological disruptions, especially in early aged ovaries.

12Nicotinamide and acetyl group of substrate reacts enzymatically in the presence of SIRT1, forming O-acetyl ADP ribose as a metabolite. This reaction generates NAD with helps the ovarian cells to grow.

13In mice model, Sirtuin regulation has been related to fertility. Mice strains with Sirtuin deficiency demonstrate a tiny phenotype with growth-related defects and early postnatal expiries. In cases of SIRT1 deficiency, Resveratrol, an indirect SIRT1 activator, demonstrated a vital role of SIRT1 as an activator of steroidogenesis during luteinization and differentiation of granulosa cells.

14Cytochrome P450, NADPH oxidase family (28) and mitochondria generate ROS during the physiological electron transport chain reactions. Mitochondrial ability to maintain the ROS is achieved by the total redox environment and its compartmentalized reduction activity, which is dependent on the antioxidant buffers (electron donors) (NADPH, NADH and glutathione). However, the antioxidants like manganese superoxide along with peroxides and mitochondrial thioredoxin cycle system counter balances the negativity. This stability is very much demanded for the maturation of ovarian follicles; otherwise, the effects are detrimental (30). SIRT1 inhibition leads to an inability of the oocyte to up-regulate SOD2 and counteract the increase in ROS under increased OS(23).

15Manganese superoxide converts the injurious free radicals (superoxides), which are capable of damaging the DNA, to oxygen molecule and hydrogen peroxide. Further, catalase converts hydrogen peroxide to water and oxygen. Normal oxidant generation is essential for various physiologic functions of the reproductive system (ovary), including ovarian steroid genesis, oocyte maturation, ovulation, blastocysts formation, implantation, luteolysis and luteal maintenance in pregnancy. However, change in this normality becomes another important regulator of ovarian germ cell growth and stromal cell physiology (31).

16Sperm cells are highly vulnerable to oxidative damages as the testicular tissue has an increased rate of cell division, mitochondrial oxygen and unsaturated fatty acid consumption, and low oxygen pressure due to the weakness of the testicular artery. SIRT1 has also been found to have a significant role in the male reproductive system. SIRT1 is involved in spermatogenesis by influencing specific functions of male germ cells, Sertoli cells, and Leydig cells. Most of these effects are due to the antioxidant effect of SIRT1 in spermatogenesis. Mostefa et al. reported OS and SIRT1 deficiency as the cause of male infertility in patients with varicocele. As varicocele also causes oxidative stress; however, the deficiency of SIRT1 has added effect of decreased seminal antioxidant defenses. The low expression of seminal SIRT1 expression has significant positive correlations with concentration, total motility, and normal morphology of sperm. There are many mechanisms by which SIRT1 modulates the antioxidant outcomes. One of these antioxidant effects is that it protects spermatozoa from apoptosis by hydrogen peroxide via ubiquitination and subsequent degradation of the transcription factor FOXO3a. SIRT1 also exerts an anti-apoptotic effect by deacetylation of lysine residues on proteins, affecting their functions, including transcriptional activity, DNA binding, protein binding, protein stability, and translocation. SIRT1 also inhibits the microglial-derived factors via the p53-caspase-3-dependent mechanism, thus abolishing the caspase-mediated apoptosis. Resveratrol reverses this effect.

17In addition to this, SIRT1 increases the expression of Bcl-2 and decreases the expression of BAX, thus regulating the mitochondrial membrane permeability, mitochondrial function, and cytochrome c release. This is the mechanism through which decrease expression of SIRT1 affects sperm motility.

18An increase in SIRT1 expression also increases nitric oxide synthase activity in vascular endothelial cells (ECs) and maintains microenvironment homeostasis, nutrient exchange, host defense reactions, and vasodilation. The mechanisms underlying this protective effect involve Sirt1/FOXOs, Sirt1/NF-κB, Sirt1/NOX, Sirt1/SOD, and Sirt1/eNOs pathways. SIRT1 plays a significant role in regulating autophagy, a stress-induced catabolic process, by increasing mitochondrial metabolism. SIRT1 also has a physiological function in acrosome biogenesis during spermiogenesis by modulating autophagic flux. SIRT1selectively activates LC3, a key initiator of autophagy. LC3 controls major steps in the autophagic pathway, including autophagic membrane growth, autophagic cargo recognition, and the fusion of autophagosomes with lysosomes. Depletion of SIRT1 in germ cells causes accumulation of acetylated LC3 in the spermatid nucleus, which affects acrosome biogenesis. These spermatogenesis changes lead to an increased proportion of abnormal spermatozoa in the SIRT1-deficient mice.

19Li et al. suggested that SIRT1 and signal transducer and activator of transcription 3 (STAT3) have a synergistic effect against oxidative stress. SIRT1 is required for regulating normal postnatal testicular development and spermatogenesis through hypothalamus-pituitary gonadotropin (HPG) signaling. SIRT1 is required for histone to protamine transition and altered chromatin condensation. Ultimately, this leads to decreased fecundity.

20It appears that many mechanisms are underlying the function of SIRT1 against oxidative stress in spermatozoa. The low expression of seminal SIRT1 expression has significant positive correlations with concentration, total motility, and normal morphology of sperm.

21SIRT1 affects insulin secretion and glucose homeostasis through its interaction with PGC-1a.. PGC-1a is one of the main transcriptional activators of glucose metabolism in the liver. SIRT1 has been shown to deacetylate PGC-1a and hence regulate hepatic glucose metabolism. Experiments on mice pancreatic beta cells have shown that SIRT1 up-regulates insulin secretion in response to glucose stimulation and enhances glucose tolerance. Also, SIRT1 knockout mice display lower serum glucose levels than wild-type mice. SIRT1 also reduces obesity by suppressing PPARg, which leads to reduced fat deposition in adipocytes. This, in turn, reduces obesity, which leads to the resolution of insulin resistance and type 2 Diabetes.

22Insulin resistance and obesity are two characteristic features of PCOS, an endocrine disorder commonly found in reproductive-age females. Compared to fertile females, females with PCOS have a higher BMI and lower levels of SIRT1. Rehana et al. hypothesized that the use of Metformin in PCOS patients might act by the correction of OS caused by SIRT1 malfunction. Adipose tissue can also secrete angiotensin II, which stimulates Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase activity, the major ROS production route in adipocytes. Thus, it can be concluded that females with low levels of SIRT1 cannot counter the excess oxidant load produced by additional adipocytes and, consequently, develop increased OS.

23Obesity is defined as a pathological increase in body fat. It is characterized by an imbalance between the intake and expenditure of calories. Various molecules have been involved in the pathogenesis of obesity, of which SIRT1 has been an important one. SIRT1 decreases adiposity and lipogenesis and increases fatty acid oxidation by repressing the peroxisome proliferator-activated receptor-gamma (PPARγ), inhibiting the CREB-regulated transcription co-activator 2 (CRTC2 or TORC2) and deacetylating and activating the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC-1α). Various studies have demonstrated low-grade, chronic inflammation in obesity, and this inflammation is the result of both macrophage recruitment and production of ROS. SIRT1 alters these macrophages’ recruitment and polarization into adipose tissues by modulating several adipokines’ expression and secretion and decreasing the risk of obesity.

24Extremes of body weight negatively affect females’ fecundability and adversely impacts fetuses and embryos through oxidative mechanisms. Moderate exercise may assist obese women in reducing weight and restoring their fertility. Lifestyle factors such as maternal smoking, alcohol consumption, and use of recreational drugs stimulate the production of unfavorable amounts of ROS, leading to OS, which renders physiological processes of female reproduction and the fetus vulnerable to oxidant-induced damage. Exposure to environmental pollution can also give rise to excessive OS during pregnancy and has increasingly raised concern about the impact of pollutant exposure on maternal and fetal health.

25Insulin resistance is defined as the resistance of target tissues such as skeletal muscles, adipocytes, and liver to insulin stimulation and is most often implicated in developing type II diabetes mellitus. Various mechanisms of the pathogenesis of insulin resistance have been proposed, of which mitochondrial dysfunction has been a popular one. Mitochondrial abnormalities, particularly mitochondrial complex 1 lead to increased reactive oxygen species production (ROS). Increased ROS leads to increased oxidative stress, impairs both B cell function and insulin signaling, thereby accelerating insulin resistance. SIRT1 restores mitochondrial complex 1 activity via the SIRT1-SIRT3-mitochondrial complex 1 pathway and alleviates mitochondrial dysfunction and OS, improving insulin resistance. SIRT1 also reduces OS by overexpression of anti-oxidative enzymes, including MnSOD and Catalase. Thus, SIRT1 may improve insulin resistance by reducing oxidative stress and regulating mitochondrial biogenesis and function.

26Cardiovascular disease due to atherosclerosis is the leading cause of death worldwide. SIRT 1 is a cardioprotective molecule that prevents atherosclerosis by modulating the various mechanisms involved in its pathogenesis, namely endothelial injury due to impaired nitric oxide (NO) production, inflammation, OS, and regulation of autophagy. SIRT1 increases endothelial NO production by activating eNOS, leading to vasodilation and reversing endothelial dysfunction. SIRT 1 also suppresses inflammation by downregulating NF-κB activity through deacetylation. SIRT 1 is noted to promote autophagy via AMPK activation, which reduces OS and inflammation and suppresses foam cell production, thereby hindering atherosclerosis progress. Lastly, SIRT1 reduces OS, a major causative factor of atherosclerosis, by its interplay with the FOXO transcription factors and up-regulation of anti-oxidative enzymes. Aging is an independent risk factor for CVD. Thus, SIRT1 acts as a cardioprotective molecule by protecting the heart from aging and ischemia/reperfusion injury, resists hypertrophic and oxidative stresses, inhibits cardiomyocyte apoptosis, and regulates cardiac energy metabolism.

27Sirtuins, including SIRT1 present in the renal system, support the production of sufficient energy throughout the different tubular and glomerular compartments to carry out all these processes (73). SIRT 1 is abundantly expressed in tubular cells and podocytes. It is also found to be highly expressed in aquaporin 2 positive cells in the distal nephron of rats, suggesting its involvement in sodium and water handling. SIRT1 inhibits sodium reabsorption in the inner medullary collecting ducts by repressing the epithelial sodium channel’s transcription (eNAC). SIRT1 also acts on the renin-angiotensin system; its overexpression downregulates angiotensin II type 1 receptor (AT1R) in vascular smooth muscle cells.

28In contrast, a reduced expression of SIRT1 is associated with the increased transcription of AT1R in podocytes. The renal medulla is a high OS zone; SIRT 1 has been shown to promote the resistance of renal medullary interstitial (RMICs) cells to oxidative stress and injury through its anti-oxidative properties. One of the mechanisms through which it does so is by increasing COX-2 and PGE2 production in RMICs. Hence, in conditions that cause ureteral obstruction, SIRT1 overexpression protects the medulla from the increased oxidative stress-induced inflammation and fibrosis by induction of COX2. SIRT1 also plays a protective role in acute kidney injury; increased ROS and mitochondrial damage are necrosis features in AKI. SIRT1 activation can alleviate the increased OS and mitochondrial dysfunction, thereby protecting the kidney against AKI-mediated necrosis. Thus, renal pathologies could result from SIRT1 mutations due to uncontrolled ROS produced by the renal tissue’s highly functional mitochondria. Evaluation of SIRT1 mutation becomes an important factor in patients with recurrent renal pathologies.

29It seems that SIRT1 has multiple roles in human pathophysiology and biochemical pathways, from its involvement in reproduction to several metabolic functions. Further research is needed to confirm its exact role in the body’s various mechanisms. There is a need to design such pharmacologic interventions that affect SIRT1 activity to bring it back to an optimal level. So, many deleterious conditions or metabolic derangements due to SIRT1 can be prevented, treated, or at least reduced in future.

30None.

31Faiza Alam: Conceptualization, Writing – original draft, designed, drafted the review, contributed to the artwork, drafted the paper, All authors approved the final version of the manuscript. Hareem Syed: Writing – original draft, drafted the paper, All authors approved the final version of the manuscript. Sofia Amjad: Writing – original draft, contributed to the artwork, drafted the paper, All authors approved the final version of the manuscript. Mukhtiar Baig: Writing – original draft, drafted the paper, All authors approved the final version of the manuscript. Taseer Ahmed Khan: critically reviewed the review, All authors approved the final version of the manuscript. Rehana Rehman: Conceptualization, Writing – original draft, conceptualized, designed, and drafted the review, contributed to the artwork, drafted the paper, All authors approved the final version of the manuscript.

32Authors have no conflict of interest to declare.