Understanding how carnitine transporters regulate sperm motility and hormone production could lead to new infertility treatments and bring hope to millions of people around the world suffering from infertility. be.
Schematic representation of carnitine transport and distribution in different tissues. Carnitine transport mediated by multiple SLCs is shown in different colors. Carnitine is shown to be transported across the epithelial cells of the intestine, kidney, and placenta to the liver, brain, heart, muscle, epididymis, and airway tissues. OCTN2 (green): Mediates carnitine transport by a sodium-dependent mechanism, but for clarity this is not reported. CT2 (purple): Particularly involved in carnitine transport in the epididymis and contributes to sperm maturation. OCTN1 (yellow): A low-affinity carnitine transporter involved in carnitine transport in various tissues. ATB0,+ (blue): mediates sodium- and chloride-dependent transport of carnitine in the intestine and other tissues, but is not reported for clarity. MCT9 (pink): A transporter involved in carnitine efflux across the basolateral membrane of absorptive epithelia such as the intestine and kidney. Arrows indicate the direction of carnitine transport across the cell membrane. This is an image created with Adobe Illustrator. The human transporter is represented as a space-fill model in AlphaFold.
A recent study published in the journal Biochemical Pharmacology outlines the role of membrane transporters in carnitine homeostasis, highlighting the molecular mechanisms involved and the implications for fertility. Carnitine is an important molecule in metabolism. It mainly promotes β-oxidation of fatty acids within mitochondria and plays an important role in maintaining metabolic flexibility. The main source of carnitine in humans is the diet, but only a small portion is synthesized endogenously. Carnitine biosynthesis requires the flux of intermediates across various organelle membranes, with the majority of carnitine synthesis occurring in the liver, with additional synthesis occurring in the kidneys and brain. Therefore, carnitine and its metabolites are distributed to tissues and organelles by membrane transporters.
The major mitochondrial carnitine shuttle system consists of two enzymes, carnitine palmitoyl transferase 1 (CPT1) and CPT2, and the carnitine/acylcarnitine carrier, a mitochondrial inner membrane transporter also known as solute carrier 25 member 20 (SLC25A20). CAC). CAC is important for transporting acylcarnitines to mitochondria for β-oxidation. Remarkably, there are no redundant mitochondrial transporters to compensate for CAC deficiency, making it essential for cell life. Other carnitine shuttles are active in the endoplasmic reticulum and peroxisomes.
Coordination of peroxisomal and mitochondrial carnitine shuttles is essential for fatty acid catabolism. Carnitine is thought to be involved in regulating the acetyl-coenzyme A (CoA)-to-CoA ratio, which has profound effects on lipid biosynthesis, gene expression, and carbohydrate metabolism. In this study, researchers reexamined the role of transporters in carnitine transport, focusing on the relationship between carnitine and fertility.
Carnitine network and changes
The distribution of carnitine is highly variable among tissues, ranging from low millimolar levels in most tissues to the highest (60 mM) levels in the testis. Many transporters are involved in maintaining carnitine homeostasis. Diet plays an important role in carnitine distribution. In fish and meat consumers, dietary carnitine accounts for approximately 75% of the total carnitine content. In contrast, vegans and vegetarians often rely heavily on endogenous synthesis and renal reabsorption to maintain carnitine levels. Without supplements, vegans and vegetarians can experience decreased carnitine levels.
Carnitine shuttle in mitochondrial fatty acid oxidation. Acyl-CoA synthase catalyzes the conversion of long-chain fatty acids to fatty acyl-CoA. These are converted to acylcarnitines by carnitine palmitoyl transferase 1 (CPT 1) located in the outer mitochondrial membrane. Acylcarnitines are transported across the inner mitochondrial membrane by carnitine/acylcarnitine carriers (CACs) in exchange for free carnitine. Once in the mitochondrial matrix, carnitine palmitoyltransferase 2 (CPT 2), located in the inner mitochondrial membrane, converts acylcarnitines to acyl-CoA and free carnitine. Free carnitine is transported to the cytosol by CAC and recycled by CPT 1. Acyl-CoA imported into the mitochondrial matrix via the carnitine shuttle undergoes β-oxidation to generate acetyl-CoA, which can then enter the body. T.C.A. This is an image created with Adobe Illustrator. hCAC is represented as a space-filling model from AlphaFold predictions.
Therefore, endogenous synthesis and reabsorption may be more relevant to homeostasis. Renal reabsorption of carnitine is the main means of compensating for dietary carnitine deficiency. Organic cation/carnitine transporter 2 (OCTN2) promotes carnitine reabsorption in the kidney. Mutations in OCTN2 cause primary carnitine deficiency disease (PCD). This disease is characterized by systemic carnitine deficiency and associated clinical symptoms such as muscle weakness, cardiomyopathy, and infertility. PCD treatment includes lifelong carnitine supplementation.
Secondary carnitine deficiency (SCD) can occur due to genetic defects in CPT2, CAC, or acyl-CoA dehydrogenase. In particular, CAC deficiency often causes life-threatening conditions due to impaired mitochondrial β-oxidation, leading to increased fatty acid accumulation in the cytoplasm. There are no extra carnitine transporters to compensate for the CAC defect. Therefore, early intervention is of paramount importance for CAC deficiency. Treatment strategies for SCD include prevention of diet-induced hypoglycemia, carnitine supplementation, and medium-chain fatty acid diet.
Carnitine and oxidative stress in infertility
Oxidative stress plays a crucial role in both male and female infertility, with reactive oxygen species (ROS) and reactive nitrogen species (RNS) contributing to lipid peroxidation, DNA fragmentation, and reduced sperm viability. Masu. Due to its antioxidant properties, carnitine scavenges free radicals and reduces oxidative damage, protecting sperm mitochondria from oxidative stress. This is especially important in maintaining sperm motility and overall fertility. This study also shows how carnitine’s antioxidant function plays a role in managing oxidative stress in female reproductive tissues such as the ovaries, where ROS imbalance can impair egg quality and disrupt the endometrial environment. Emphasizes what’s important.
human infertility
Globally, infertility is a major concern, affecting more than 180 million couples. Historically, it was thought to be primarily caused by women. However, modern insights highlight the important contributions of men. Despite advances in diagnosis, the causes of infertility often remain unknown. Mitochondrial dysfunction has emerged as a common factor in both male and female infertility, linking energy metabolism and reproductive health. Lifestyle choices influence fertility, and there is evidence that alcohol, obesity, and smoking are associated with decreased semen quality and ovulatory function.
Furthermore, although multiple studies have been conducted on the relationship between carnitine and male fertility, the underlying molecular mechanism remains unclear. In the male reproductive system, carnitine promotes mitochondrial energy metabolism, particularly by regulating the acetylcarnitine/CoA ratio, which is presumed to be involved in sperm concentration and motility. This regulation is particularly important in sperm maturation, where carnitine concentration increases dramatically from the epididymal head (5 mM) to the caudal region (60 mM).
Some studies suggest that luminal carnitine may stabilize the sperm plasma membrane, increase viability, and alleviate acrosome-reacted sperm, which is important for successful fertilization.
The role of carnitine in women is less clear. However, carnitine is involved in the energy supply necessary for ovulation, folliculogenesis, and embryonic development. Mitochondrial dysfunction, exacerbated by carnitine deficiency, is thought to be involved in conditions such as polycystic ovary syndrome (PCOS) and endometriosis. Therefore, carnitine deficiency can lead to suboptimal energy, compromised oocyte quality, and decreased fertilization potential. Additionally, carnitine has been shown to influence the production of sex hormones such as testosterone, estrogen, and progesterone, which are important for reproductive health.
SLC within the carnitine network
Studies have shown that OCTN1 may function as a carnitine transporter in tissues with high carnitine levels, such as the epididymis. However, the direct relationship between OCTN1 and infertility has not been studied so far. OCTN2 is the highest affinity carnitine transporter. It is ubiquitously expressed in the heart, skeletal muscle, kidney, and intestine. Mutations in OCTN2 are associated with Crohn’s disease (CD) due to carnitine deficiency in the intestinal epithelium. Furthermore, mutations in OCTN2 can cause fertility problems by disrupting carnitine homeostasis in the reproductive system, particularly in the epididymis. In the male reproductive system, carnitine transporter 2 (CT2) is localized to the luminal membrane of epididymal cells and the plasma membrane of Sertoli cells in the testis. In women, CT2 is highly expressed in the endometrium.
CT2 localization in the testis is the main molecular link between male infertility and carnitine. However, it is not clear whether carnitine is present in the endometrium or testis and whether carnitine is associated with transporter regulation or energy requirements. CAC is a protein essential for maintaining cell life. Although this study points to a potential role for CAC in infertility, no directly causative mutations linking CAC and reproductive dysfunction have yet been identified.
clinical significance
The study concludes by suggesting potential therapeutic avenues. Carnitine supplementation holds promise for improving sperm motility and morphology in cases of idiopathic infertility, while carnitine’s role in antioxidant defense highlights its therapeutic potential in oxidative stress-related reproductive disorders . Recognizing the role of carnitine and SLC in sperm motility and energy metabolism may aid in the development of more sophisticated advanced diagnostic tools and targeted therapies. Further research is needed to understand the precise molecular mechanisms linking carnitine transporters and reproductive health, which could lead to new treatments for both male and female infertility.
