Navigating the Electron Transport Chain: Your Guide to Cellular Energy Production
This blog post delves into the intricate workings of the electron transport chain (ETC), a crucial process for energy production within our cells.
The Electron Transport Chain: A Cellular Powerhouse
The electron transport chain represents the final common pathway in aerobic cells, facilitating the transfer of electrons from various substrates to oxygen, ultimately generating energy.
Substrate Oxidation and Electron Carriers
Diverse substrates can utilize this pathway due to their oxidation by enzymes that employ NAD+ or FAD as electron acceptor cofactors. The resulting reduced NADH and FADH2 molecules then donate electrons to the electron transport chain.
Here’s a breakdown of the key players:
NADH Sources:
- Isocitrate, α-ketoglutarate, and malate dehydrogenase (TCA cycle)
- Pyruvate dehydrogenase
- L-3-Hydroxylacyl coenzyme A (CoA) dehydrogenase (fatty acid oxidation)
- Miscellaneous NAD+-linked dehydrogenases
FADH2 Sources:
- Succinate dehydrogenase (TCA cycle)
- FAD-linked dehydrogenase of glyceraldehyde-3-phosphate shuttle
- Acyl CoA dehydrogenase (fatty acid oxidation)
- Miscellaneous FAD-linked dehydrogenases
Transporting NADH: The Malate-Aspartate Shuttle
The mitochondrial membrane presents a barrier to NADH. To overcome this, NADH equivalents generated in glycolysis are transported from the cytoplasm to the mitochondria for oxidation via the malate-aspartate shuttle. This shuttle system, primarily operational in the liver, kidney, and heart, relies on the enzymes malate dehydrogenase (MDH) and aspartate aminotransferase.
Components and Organization of the Electron Transport Chain
All components of the ETC reside within the inner mitochondrial membrane, organized into four multi-protein complexes (I-IV) interconnected by coenzyme Q and cytochrome c, two mobile carriers.
Complex I (NADH-Coenzyme Q Reductase):
- Entry point: Electrons from NADH
- Prosthetic groups: Flavin mononucleotide (FMN), Iron-sulfur (Fe-S) centers
- Electron acceptor: Coenzyme Q (ubiquinone)
- Electron transfer path: NADH > FMN > Fe-S > Q
- Energy yield: 12 kcal/mol (drives 4 protons out of the mitochondria)
- Inhibitors: Rotenone, barbiturates (amobarbital, secobarbital), Piericidine A
Complex II (Succinate-Coenzyme Q Reductase):
- Entry point: Electrons from succinate
- Prosthetic groups: FAD, Fe-S centers
- Electron acceptor: Coenzyme Q
- Electron transfer path: Succinate > FAD > FeS > Q
- Note: Insufficient energy release for proton pumping
- Inhibitors: Carboxin
Coenzyme Q (Ubiquinone):
- Accepts electrons from: Complex I and Complex II
- Donates electrons to: Complex III
- Reduction states: Q (ubiquinone) > QH (semiquinone) > QH2 (quinol)
Complex III (Coenzyme Q-Cytochrome c Reductase):
- Electron acceptor: Cytochrome c
- Prosthetic group: Heme (cytochrome b, cytochrome c1)
- Electron transfer path: Q > Fe-S > cytochrome b > cytochrome c1 > cytochrome c
- Energy yield: 10 kcal/mol (pumps 4 protons out)
- Inhibitors: Antimycin A
Cytochrome c:
- Mediates electron transfer: Complex III to Complex IV
- Prosthetic group: Heme
Complex IV (Cytochrome c Oxidase):
- Electron acceptor: Molecular oxygen (O2), producing water
- Prosthetic groups: Copper, Heme (cytochrome a, cytochrome a3)
- Electron transfer path: Cytochrome c > cytochrome a+a3 > O2
- Proton pumping: 2 protons pumped out
- Inhibitors: Carbon monoxide (CO), Hydrogen sulfide (H2S), Azide, Cyanide (CN-)
Overall Electron Flow:
F1 is tightly bound to F0 and sits on the matrix side of the mitochondrial membrane.
The F1 unit is composed of five subunits. It contains the catalytic site for ATP synthesis. Inhibitors of ATP synthase include;
- Oligomycin, an antibiotic
- Dicyclohexylcarbodiimide (DCCD)
Other enzymes that can couple ATP synthesis to the transport of ions other than hydrogen down a concentration gradient are found in other parts of the cell:
- The Ca2+-ATPase of the sarcoplasmic reticulum
- The Na+K+-ATPase of the plasma membrane
ADP must be transported into the mitochondrial matrix to be used for ATP synthesis, and ATP produced in the mitochondria must be transported out for use by the cell. A membrane-bound transporter system catalyzes the exchange of ADP and ATP across the membrane. Inhibitors of the ADP/ATP transporter include:
- Atractyloside
- Bongkrekic acid
These are compounds that allow normal function of the electron transport chain without the production of ATP. Uncouplers cause leakage or transport of H+ across the membrane that collapses the proton gradient before it can be used for ATP synthesis. Energy still may be released as the electrons are transferred down the transport chain; however, this energy is not trapped as ATP but appears instead as heat. Oxidative phosphorylation uncouplers include:
- 2,4-Dinitrophenol, which was once used as a weight-loss drug but was discontinued because of its toxicity
- Dicumarol, which is an anticoagulant
- Chlorocarbonylcyanide phenylhydrazone (CCCP), which is a compound that carries protons across the membrane
- Bilirubin, which is a metabolite of heme degradation but is not normally present in mitochondria in concentrations high enough to affect normal function
The mitochondria of brown fats contain thermogenin, which also uncouples oxidative phosphorylation leading to the release of the energy as heat.
