Browsing Pathways

ABSTRACT: Pancreatitis is an inflammation of the pancreas, a gland located behind the stomach that plays a crucial role in digestion and blood sugar regulation. The pancreas produces enzymes that help break down food in the intestines and hormones like insulin that regulate blood sugar levels, can be classified into acute and chronic forms. Acute pancreatitis is characterized by sudden inflammation, while chronic pancreatitis involves extensive stromal formation and immune cell infiltration, including neutrophils, eosinophils, monocytes, macrophages, and pancreatic stellate cells (PSCs). These inflammatory cells play a crucial role in driving inflammation and fibrosis, a significant risk factor for pancreatic cancer. This review examines the role of various cytokines and molecular signaling pathways in pancreatitis pathogenesis. Key cytokines such as IL-1, IL1β, IL-6, IL-8, IL-10, IL-18, IL-33, and TNF-α are implicated in disease progression. The review focuses on critical signaling pathways: Transforming Growth Factor-β/SMAD, Mitogen-Activated Protein Kinases (MAPK), Rho Kinase, Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT), and Phosphatidylinositol 3-Kinase (PI3K). It highlights the involvement of these pathways in PSC activation and pancreatic fibrosis, and discusses the importance of experimental models in understanding these mechanisms. The review underscores the need for further research to elucidate these pathways’ complexities and their potential for developing targeted therapies. PATHOGENESIS OF PANCREATITIS: 1. Enzyme Activation and Autodigestion: Under normal conditions, the pancreas produces digestive enzymes in an inactive form (zymogens), which are activated only in the small intestine. In pancreatitis, these zymogens, particularly trypsinogen, are converted to active trypsin within the pancreas itself. This premature activation triggers the autodigestion of pancreatic tissue, damaging cells and leading to the release of inflammatory mediators. 2. Ductal Obstruction: Bile duct obstruction, often caused by gallstones, is a common cause of acute pancreatitis. The obstruction leads to increased intraductal pressure, which can cause the reflux of bile into the pancreatic ducts. This bile reflux can contribute to the premature activation of digestive enzymes within the pancreas, setting off the inflammatory process. 3. Alcohol-Induced Pancreatitis: Chronic alcohol consumption is a major risk factor for pancreatitis. Alcohol can increase the production of pancreatic enzymes and sensitize the pancreas to other injury triggers. Additionally, alcohol metabolism within the pancreas generates toxic metabolites, such as acetaldehyde and fatty acid ethyl esters, which further contribute to cellular injury and inflammation. 4. Inflammatory Response: The autodigestion of pancreatic tissue by prematurely activated enzymes releases a variety of pro-inflammatory cytokines and chemokines, leading to local inflammation. In severe cases, this local inflammation can spread systemically, causing a systemic inflammatory response syndrome (SIRS). This widespread inflammation can result in multiorgan dysfunction, including respiratory, renal, and cardiovascular failure. 5. Oxidative Stress: Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and the body's antioxidant defenses, plays a crucial role in the pathogenesis of pancreatitis. ROS can damage cellular membranes, proteins, and DNA, exacerbating the inflammatory response and cellular injury. 6. Genetic Factors: Genetic mutations, particularly in the PRSS1 (cationic trypsinogen) and SPINK1 (serine protease inhibitor) genes, can predispose individuals to pancreatitis. Mutations in PRSS1 can lead to the production of a trypsinogen variant that is more prone to premature activation, while SPINK1 mutations can reduce the effectiveness of trypsin inhibition, allowing unchecked trypsin activity and increasing the risk of pancreatitis. PATHWAYS INVOLVED IN PANCREATITIS: • TGF-β1/SMAD pathway: The TGF-β1/SMAD pathway plays a critical role in regulating immune responses, cell growth, differentiation, and apoptosis. In mammals, TGF-β exists in three isoforms (TGF-β1, TGF-β2, and TGF-β3), and it mediates its effects by binding to specific receptors, activating SMAD proteins that translocate to the nucleus to regulate gene transcription. TGF-β is implicated in the pathogenesis of acute and chronic pancreatitis and pancreatic fibrosis, particularly through the activation and proliferation of pancreatic stellate cells (PSCs). Studies show that TGF-β signaling is essential for cerulein-induced pancreatitis and that disrupting this pathway can reduce fibrosis or lead to autoimmune pancreatitis, highlighting its dual role in both disease progression and immune homeostasis. Additionally, TGF-α, another growth factor, has been shown to enhance PSC activity and contribute to chronic pancreatitis. While TGF-β is known to activate both SMAD-dependent and independent pathways, including MAPK and PI3-kinase, the precise mechanisms remain incompletely understood. • MAPK pathway: MAPK pathways, including ERK, JNK, and p38, are crucial in regulating cell proliferation, survival, apoptosis, and cytokine production. In alcohol-induced pancreatic injury, ethanol and acetaldehyde activate MAPK and AP-1 signaling in pancreatic stellate cells (PSCs), contributing to fibrosis. Ethanol also promotes CX3CL1 release via ERK activation, while oxidative stress and PDGF activate MAPK pathways and enhance PSC activity. Additionally, PAR-2 agonists increase collagen synthesis through JNK and p38 pathways, implicating them in pancreatic fibrosis. Inhibiting the MEK-1/ERK pathway, as shown with PD98059, can protect against pancreatitis, suggesting potential therapeutic targets. Although these studies enhance our understanding of MAPK's role in pancreatitis-associated fibrosis, further research is needed to explore the interplay between different signaling pathways. • RHO KINASE pathway: In chronic pancreatitis, the activation of pancreatic stellate cells (PSCs) and stress fiber formation involve cytoskeletal reorganization regulated by Rho family proteins (RhoA, Rac, Cdc42). Inhibiting RhoA and Rho kinase reduces PSC activity, including α-SMA, proliferation, and collagen production. In cerulein-induced pancreatitis, Rho kinase inhibitors like Y-27632 increase serum amylase and tissue damage but prevent recovery of ROCK-II, suggesting Rho kinase's role in pancreatic enzyme secretion and inflammation. These findings point to Rho kinase as a potential therapeutic target for pancreatitis, warranting further research. • PI3K-Akt pathway: The PI3K-Akt pathway, activated by growth factors, regulates cell growth, survival, apoptosis, and inflammation. Inhibiting this pathway with wortmannin has been shown to reduce trypsinogen activation and decrease inflammatory cytokines in acute pancreatitis. The PI3Kγ isoform specifically influences pancreatic acinar cell responses in pancreatitis. Studies show that mice lacking PI3Kγ are protected from acinar cell injury and exhibit less severe pancreatitis, suggesting that PI3K inhibitors could be a potential therapy for treating acute pancreatitis. • JAK/STAT signaling pathway: The JAK/STAT signaling pathway controls cell proliferation, differentiation, and inflammation, playing a key role in pancreatitis. IL-6, a pro-inflammatory cytokine, acts through this pathway and is elevated in pancreatitis patients. In vitro studies show that IL-6 secretion is induced by various inflammatory mediators, highlighting its role in acute pancreatitis. Blocking IL-6 reduces STAT-3 activation, decreases pancreatitis severity, and promotes pancreatic acinar cell apoptosis. Additionally, the JAK-2/STAT-3 pathway drives PSC proliferation, while inhibiting JAK-1/STAT-1 lessens pancreatic injury, suggesting JAK/STAT as a potential target for treating pancreatitis. • NLRP3/NF-κB Pathway: An important part of the pathogenesis of pancreatitis is the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. A transcription factor called NF-κB controls the expression of several genes related to inflammation, immunological responses, cell survival, and apoptosis. The NACHT, LRR, and PYD domains are components of the protein complex known as the NLRP3 inflammasome. It aids in the synthesis of IL-18 and IL-1β. Inflammatory cytokines are released when NF-κB is engaged because it contributes to the production of reactive molecules (ROS), which in turn activate the NLRP3 inflammasome. Toll-like receptor 4 (TLR4) plays a crucial role in NF-κB activation. Without it, inflammation is decreased, potentially reducing damage to the pancreas and lungs. Some drugs can lower inflammation by focusing on certain pathways: • By preventing the activation of NLRP3 and NF-κB, surfactant protein D (SP-D) can shield the pancreas and lungs. • A substance found in liquorice called isoflavonopoietin (ISL) can reduce inflammation by blocking the activation of NLRP3 and NF-κB. • Ethylpyruvate also inhibits NF-κB, which lowers inflammation and guards against lung damage from severe pancreatitis. • PKC Pathway: A member of the phospholipid-dependent serine/threonine kinase family is protein kinase C (PKC). There are at least a few different isoforms of it. Pancreatic follicular cells have been found to include four PKC isoforms (α, δ, ε, and ζ), each with a distinct activation pattern, as well as conventional PKC alleles (α, βI, βII, and β), novel PKC isoforms (δ, ε, η, and θ), and other PKC isoforms (λ subclass, γ subclass). According to experimental research, the lung overproduces and releases inflammatory mediators via a PKC-dependent mechanism. Inflammatory cytokines can activate the PKC pathway, a crucial signaling system. A key inflammatory response protein that is markedly overexpressed in ALI, src-inhibited C kinase substrate (SSeCKS) is a PKC substrate that preferentially interacts to signaling proteins like PKC to impair endothelial cell permeability. By altering its downstream substrate SSeCKS, the PKC pathway controls the activity of cytoskeletal proteins and the function of the endothelial cell barrier. F-actin is activated by PKC-mediated overexpression of SSeCKS, which causes NF-κB to be activated in HPMEC, ultimately leading to ALI. We hypothesize that NF-κB may be a crucial mediator of apoptosis, AVP-5/MMP-9, and PKC/SSeCKS/F-actin signaling pathways during AP-induced ALI since restoration of aquaporin 5 (AQP-5) and matrix metalloproteinase 9 (MMP-9) and prevention of apoptosis may result in NF-κB attenuation. Via the PKCα/MAPK pathway, SP controls the synthesis of LTB4, which in turn stimulates AP-ALI through neutrophil TEM. By blocking the PKC/SSeCKS signaling pathway, LXA4 efficiently stimulates F-actin remodeling and controls its expression in pulmonary microvascular endothelial cells both in vivo and in vitro. • NPs-LAMC2-Neutrophil Pathway: Laminin gamma 2 (LAMC2) and Serpin Family A Member 1 (SERPINA1) are linked to leukocyte-cell adhesion, the control of endopeptidases, and the extracellular matrix that contains collagen. There is a suggestion that the cleavage of NP enzymes releases the LAMC2 fragment, which crucially encourages the recruitment of neutrophils. In the acute phase, this would cause NP to be produced. It has been noted that LAMC2 is overexpressed and linked to the initial phases of ALI. Neutrophils, LAMC2, and NPs may therefore create positive feedback loops in the pathophysiology of SAPALI. It is possible that the upregulation of LAMC2 expression in SAP-ALI lung tissue results from elevated LAMC2 expression in SAP-ALI lung tissue. One serine protease inhibitor that adversely affects NP activity is SERPINA1. Serine protease inhibitor B1 (serpinB1) is highly expressed in SAP-ALI lung tissue, and it may be a new biomarker of disease severity due to its potential correlation with the lung's high neutrophil and monocyte aggregation. By inhibiting NPsLAMC2 and adversely controlling NP activity in SAP-ALI, emodin may have a protective impact. The AP-induced ALI is considerably reduced by neutrophil-altered loops. • P2X7 Pathway Proinflammatory cytokines are released in significant quantities from injured glandular follicle cells in SAP, a sterile inflammatory disease. The purinergic receptor P2X7 is a crucial molecule involved in the inflammatory response and a member of the P2X family of ATP-gated cation channels. Numerous signaling pathways, including NF-κB, MAPKs, and reactive oxygen species (ROS), are stimulated by P2X7 activation and generate significant amounts of inflammatory mediators. Recent research has demonstrated that P2X7 can successfully promote NLRP3's inflammatory activation. P2X7R controls calcium signaling and ion transport and is primarily expressed in rodent pancreatic ductal cells, according to numerous studies. Cabili et al. discovered evidence that the exocrine glands of animals also express NLRP3 receptors. Pancreatic duct cells produce significant levels of different P2 receptors, particularly P2X7 receptors, although the alveoli in the pancreas show poor functioning and a noticeable paucity of P2X7 receptors for purinergic receptor signaling. Furthermore, SAP is typically aseptic at first, which increases the risk of glandular follicle cell necrosis. Through the action of plasma membrane P2X7 receptors, damage-associated molecular patterns (DAMP), which are generated from necrotic glandular follicle cells, trigger a sterile inflammatory response that predisposes mice to pancreatic injury. Furthermore, 12 hours following pancreatic damage, the P2X7/NLRP3 pathway is triggered. Nonetheless, inflammation is mostly time-course dependent, indicating that the degree of pancreatitis is correlated with P2X7 induction. • NRF2 SIGNAL TRANSDUCTION PATHWAY: One survival strategy for reducing oxidative damage is believed to be the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. The protective antioxidant Nrf2 controls the homeostasis of cellular oxidation and reduction. SAP can be treated by modulating the Nrf2 pathway in response to oxidative stress .One key tactic to prevent ROS production and manage oxidative stress is Nrf2 activation. Moreover, Nrf2 is a crucial regulator in ALI. When the cell is at rest, Nrf2 is a part of the cytoplasm and attaches itself to Kelch-like ECH-associated protein 1 (Keap1), which is eventually broken down. Nevertheless, Nrf2 separates from Keap1 in response to oxidative stress. This can be accomplished by a number of methods, including phosphorylation of particular Nrf2 amino acid residues via multiple protein kinase pathways and oxidative modification of cysteine thiols in classical Keap1. Because of its connection to redox homeostasis and energy metabolism, the intracellular energy sensor AMP-activated protein kinase (AMPK) is a kinase that is thought to be upstream of Nrf2. Additionally, Akt kinase and glycogen synthase kinase 3 beta (GSK3β) may be involved in another way of AMPK-mediated Nrf2 activation. Furthermore, as a strong anti-inflammatory and new antioxidant mediator, LXA4 in HPMEC can further enhance Nrf2 production. TNF-α can also activate the Nrf2 signalling pathway and its downstream gene, HO-1. By controlling the Nrf2 pathway, LXA4 may reduce ROS and inflammation brought on by AP. By activating Nrf2, Isoliquiritigenin , a chalcone structure (4,20,40-trihydroxy chalcone), can be administered intraperitoneally to treat ALI/Acute Respiratory Distress Syndrome (ARDS) linked to gram-negative bacterial infections.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.