Electron Transport Chain and Oxidative Phosphorylation

Electron Transport Chain

• Electron transport chain (ETC) consists of four protein complexes located in the inner mitochondrial membrane.
• Complex I (NADH Dehydrogenase Complex): Transfers electrons from NADH to coenzyme Q (UQ) and pumps four protons (H+) from the matrix into the intermembrane space.
• Complex II (Succinate Dehydrogenase Complex): Transfers electrons from FADH2 to UQ without pumping protons.
• Complex III (Cytochrome bc1 Complex): Transfers electrons from reduced UQ (UQH2) to cytochrome c, one electron at a time.
• Complex IV (Cytochrome C Oxidase): Catalyzes the transfer of four electrons to oxygen, producing water (H2O).

Oxidative Phosphorylation and ROS Formation

• Reactive oxygen species (ROS) are formed during the electron transport chain due to electron leaks.
• These leaks occur when electrons exit the ETC while being transferred by Complex I or Complex III.
• The leaked electrons react with oxygen, generating superoxide radical (O2-), which can further convert to Hydrogen Peroxide (H2O2) and Hydroxyl Radical (OH).

Reactive Nitrogen Species (RNS)

• Reactive nitrogen species (RNS) include:
  • Nitric Oxide (NO-) which has a signaling function.
  • Nitrogen dioxide (NO2).
  • Peroxynitrite (ONOO-), which damages proteins and nucleic acids.
• O2- reacts with NO- to form ONOO-.

Radical Chain Reaction

• Lipid peroxidation reactions can be initiated with the abstraction of a hydrogen atom from an unsaturated fatty acid.
• Lipid radical reacts with O2 forming a peroxyl radical, which further reacts with another fatty acid, leading to a chain reaction.
• Transition metals like Fe2+ can initiate further radical formation.
• Lipid peroxidation can result in the formation of α,β-unsaturated aldehyde, which involves a radical cleavage reaction.

Respiratory Burst

• ROS are also produced during respiratory burst within macrophages and neutrophils.
• During phagocytosis, these cells produce large quantities of ROS to kill pathogens.
• NADPH oxidase on phagolysosome membranes converts O2 to O2-.
• O2- reacts with molecules to generate various free radicals that destroy bacteria.

Antioxidants

• Living organisms have developed defense mechanisms to protect against oxidative stress, called antioxidants.
• Enzyme systems:
  • Superoxide dismutase (SOD): Catalyzes the conversion of superoxide radical into H2O2 and O2.
  • Catalase: Degrades H2O2 into H2O and O2.
  • Glutathione-centered system: Uses GSH to reduce H2O2 and organic peroxides.
  • Thioredoxin-centered system.
• Molecule systems:
  • α-Tocopherol (Vitamin E)
  • β-carotene (Vitamin A)
  • Ascorbic acid (Vitamin C)

Lipid Digestion

• Dietary fat is mainly composed of triacylglycerols (TG), along with phospholipids and cholesterol.
• Lipid digestion and absorption occurs in the small intestine.
• Bile salts emulsify dietary fat in the intestine, forming micelles.
• Pancreas secretes lipase and phospholipase A2 (PLA2).
• PLA2 digests the ester bond at C2 of the dietary phospholipids, releasing one free fatty acid and lysophosphatidate.
• Pancreatic lipase digests the ester bonds at C1 and C3 of the dietary triacylglycerols, releasing two free fatty acids and a monoacylglycerol.

Lipid Absorption

• Free fatty acids (FFAs), monoacylglycerols, lysophosphatides, and cholesterol form mixed micelles and are absorbed freely into the intestinal cells.
• Inside the cells, FFA are activated to form acyl-CoA.
• Acyl-CoA is reassembled with monoacylglycerol to synthesize triacylglycerol.
• Acyl-CoA is reassembled with lysophosphatides to synthesize phospholipids.
• Newly synthesized triacylglycerols, phospholipids, cholesterol, and ApoProtein-B48 are packaged into nascent chylomicrons.

Chylomicrons/Lipoproteins

• Chylomicrons, also called lipoproteins, are composed of lipids, cholesterol, cholesterol esters, and proteins.
• They are classified based on their density.

Fatty Acid Activation by Coenzyme-A

• Fatty acids are activated by Coenzyme-A to form acyl-CoA.

Triglyceride Synthesis

• Triglycerides are synthesized by combining two acyl-CoA with a monoacylglycerol.

Phospholipid Synthesis

• Phospholipids are synthesized by reassembling FFA with lysophosphatides inside intestinal cells.