2024-25 FFP1 Electron Transport Chain

Electron Transport Chain (ETC)

Overview

  • Final pathway for reduced coenzymes (NADH and FADH2) produced during catabolism.

  • Electrons are passed down the ETC, releasing energy that helps generate ATP.

  • Energy not converted to ATP but used to transport Ca2+ and generate heat.

Coenzymes

    • NAD+ + 2H+ + 2e- → NADH + H+

    • FAD + 2H+ + 2e- → FADH2

  • Electrons are crucial for ATP generation.

Mechanism of Energy Harvesting

  • The cell makes energy using the ETC, which consists of proteins embedded in the inner mitochondrial membrane.

  • The ETC facilitates the transfer of electrons to produce ATP, catalyzed by the enzyme ATP synthase:

    • ADP + Pi → ATP.

Mitochondrial Structure

Substrate Shuttles

  • Shuttle Systems: Transport NADH produced in glycolysis into the mitochondria, the inner membrane lacks an NADH transport protein.

    • Glycerol 3-phosphate shuttle: Electrons from cytosolic NADH are transferred to mitochondrial FAD.

    • Malate-aspartate shuttle: Electrons from cytosolic NADH are transferred to mitochondrial NAD+.

3 Multi protein Complexes in the Inner Mitochondrial membrane

  1. NADH-Q reductase complex

  2. Cytochrome C reductase complex

  3. Cytochrome C oxidase

Complexes in the Electron Transport Chain

Overview of Complexes I-IV

  • Complex I (NADH-Q reductase complex): Transfers electrons from NADH to CoQ.

  • Complex II (Succinate dehydrogenase): Transfers electrons from succinate to CoQ.

  • Complex III: Transfers electrons from ubiquinol to cytochrome C.

  • Complex IV (Cytochrome C oxidase): Transfers electrons from cytochrome C to oxygen, forming water.

Electron Transfer and Energy Release

  • The energy is used to pump protons (H+) across the inner mitochondrial membrane, creating a proton gradient:

    • NADH yields 3 ATP (3 sites of proton pumping).

    • FADH2 yields 2 ATP (2 sites of proton pumping).

Oxidative Phosphorylation

  • Oxygen serves as the final electron acceptor in the ETC.

  • The proton gradient causes protons to move back into the mitochondrial matrix, through ATP synthase.

  • ATP synthase uses the energy from this proton flow to produce ATP.

Chemiosmotic Hypothesis

  1. Protons are pumped from the mitochondrial matrix to the intermembrane space

  2. The proton gradient drives ATP synthesis as protons flow back into the matrix through ATP synthase.

Uncoupling Proteins (UCP)

  • UCPs located in the inner mitochondrial membrane create a proton leak, releasing energy as heat.

  • Thermogenin (UCP1) aids heat production in brown adipose tissue, compensating for cold exposure.

  • Considerable energy is expended and not stored as ATP in this process.

Synthetic Uncouplers

  • Compounds like 2,4-dinitrophenol disrupt ATP synthesis by increasing the inner mitochondrial membrane's permeability.

Kernicterus - rare neurological disorder of hyperbillirubinemia during infancy if jaundice untreated

Mitochondrial Diseases

  • OXPHOS Diseases: Caused by mutations affecting the electron transport chain complexes.

    • Affects high energy-demand tissues (heart, muscle, nervous tissue).

  • Leber Hereditary Optic Neuropathy: Sudden blindness in young adults, linked to mutations in NADH-Q reductase, cytochrome C reductase, or cytochrome oxidase subunits.

  • Inhibition of ETC complexes can lead to inhibition of ATP synthesis and cell death

Vitamin Deficiencies

  • Niacin (B3) and Riboflavin (B2) are essential for coenzymes NAD and FAD, respectively.

  • Deficiencies can cause severe lethargy and fatigue along with various systemic complications.