Peroxisomes Overview and Function

Peroxisomes

• Peroxisomes are organelles that contain enzymes to rid cells of toxic substances, specifically hydrogen peroxide.
• Hydrogen peroxide is a byproduct of cellular metabolism.
• They convert hydrogen peroxide into water, making the toxic substance safe.
• Some peroxisomes, like those in liver cells, detoxify alcohol and other harmful substances by transferring hydrogen from toxins to oxygen molecules (oxidation).
• Others are crucial for phospholipid production, which is vital for membrane formation.

Peroxisome Structure and Function

• Peroxisomes have a single membrane.
• The core contains enzymes involved in specific metabolic pathways.
• They self-replicate, unlike mitochondria.
• Peroxisomes obtain needed proteins from the surrounding cytosol. This process of obtaining proteins from the cytosol isn't fully understood but requires specific targeting signals found in amino acid sequences.
• These signals attach to receptor proteins in the cytosol and docking proteins in the peroxisome membrane.

Peroxisomal Disorders

• Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes encoding peroxins, proteins essential for normal peroxisome assembly.
• Mutations in related PEX genes often cause deficiencies in peroxisome function.
• Affected individuals often have characteristic facial abnormalities (e.g., high forehead, frontal bossing, small face, low-set ears, and slanted eyes).
• They commonly present with hypotonia (floppy muscles), developmental delays, and mental retardation.
• Peroxisomal disorders can lead to an accumulation of very long-chain fatty acids (VLCFAs) and branched-chain fatty acids (BCFAs) within tissues and cells, potentially impairing multiple organ systems.
• Reduced levels of plasmalogens (ether-phospholipids) in brain and lung tissue are often seen.

Oral Glucose Tolerance Test (OGTT)

• The OGTT measures blood glucose levels after consuming glucose. The test gauges how well the body regulates blood glucose after glucose consumption.
• Blood glucose levels are measured at various time points after glucose ingestion.
• Corresponding insulin levels are measured at the same time points to see the immediate response of the body's endocrine system.
• A graph of blood glucose versus time is plotted, and normal/abnormal results can be noted.

Glucose Homeostasis

• Glucose homeostasis is regulated primarily through the actions of insulin and glucagon.
• Insulin, released from the pancreas’ beta cells, reduces blood glucose levels. It aids glucose uptake into cells and encourages glycogen storage.
• Glucagon, released from alpha cells in the pancreas, increases circulating glucose. It stimulates glycogen breakdown in the liver, enhancing gluconeogenesis.

Type 1 Diabetes

• Type 1 diabetes results from an autoimmune attack of insulin producing beta cells in the pancreas. Beta cells no longer produce sufficient insulin.
• In type 1 diabetes, the body cannot appropriately regulate blood sugar or utilize glucose for energy.

Insulin Secretion

• The release of insulin into the blood is a complex process in response to elevated blood glucose levels.
• The glucose uptake into beta cells leads to metabolic pathways. The result leads to membrane depolarization, which prompts the opening of calcium channels.
• The influx of calcium ions triggers the release of insulin granules into the blood stream.

GLUT4 Translocation

• Insulin promotes glucose uptake by activating the translocation of glucose transporters (e.g., GLUT4) to the cell membrane.
• Muscle cells and adipocytes require insulin for glucose uptake, meaning the proper function and release of insulin is necessary for these cells to respond to glucose.
• The absence of insulin prevents the recruitment of GLUT4 to the membrane impeding the ability of these cells to use glucose for energy.

Glucagon Regulation

• Glucagon, produced by alpha cells in the pancreas, is fundamental in regulating the homeostasis of glucose levels.
• Glucagon is triggered by hypoglycemia (low blood glucose) and acts on the liver in response to lower than normal blood glucose levels.
• Glucagon increases blood glucose through stimulating glycogenolysis (glycogen breakdown) and gluconeogenesis (formation of glucose).
• Increased glucagon results in increased glucose in the blood.

Glucagon Signaling in the Liver

• Glucagon signaling in the liver mainly occurs through a G-protein coupled receptor (GPCR) pathway which utilizes protein kinases (e.g., PKA).
• Glucagon binds to the liver receptor causing a cascade of intracellular events.
• The subsequent actions decrease glycogen stores and increase glycogen production (gluconeogenesis), increasing glucose in the blood.
• Pyruvate and lactate are crucial substrates for gluconeogenesis, offering vital building blocks for sugar production.