Electron Transport Chain 

Overview – Electron Transport Chain 

• Function 
  • couple energy stored in electron acceptors (NADH, FADH₂) to ATP synthesis
    • process called oxidative phosphorylation
      • 3 ATPs per NADH 
        • NADH enters mitochondria from production in cytosol via
          • malate-aspartate shuttle
          • glycerol-3-phosphate shuttle
      • 2 ATPs per FADH₂
        • lower energy content than NADH
• Pathway
  • located in inner mitochondrial membrane
  • series of carrier enzymes
    • NADH and FADH₂ create a proton gradient across the inner membrane
    • pass electrons in a stepwise fashion
    • oxygen is the final electron acceptor
    • flow of proton back down concentration gradient drives F₀F₁ ATP synthase complex
      • net production of ATP
• Clinical importance
  • electron transport inhibitors
    • disrupt membrane bound carrier enzymes
      • result
        • ↓ proton gradient
        • ↓ ATP synthesis
        • ↓ O₂ consumption
        • ↑ intracellular NADH/NAD+ ratio
    • CO
      • source
        • combustion (smoking, fires, car exhaust, grills)
        • paint strippers
      • presentation
        • pulse oximeter may read 100% sat but actually O₂ sat is ↓
          • pulse oximeters will read both the CO and O₂ as saturating hemoglobin
          • patients exposed to CO must use a co-oximeter (that also detects carboxyhemoglobin)
        • cherry-red lips and cheeks
        • headache/nausea
        • tachypnea
        • tachycardia
      • treatment
        • 100% O₂
    • CN
      • source
        • nitroprusside administration
          • byproduct
          • give with thiosulfate to consume produced CN
        • combustion of polyurethane
          • burning furniture, mattresses
        • Mining (gold), metal extraction
      • presentation
        • seizures, tachypnea, tachycardia, headache, flushing
      • treatment
        • sodium thiosulfate
          • forms thiocyanate, less-toxic metabolite, renally excreted
        • nitrites
          • convert hemoglobin to methemoglobin (ferrous to ferric)
          • does not allow cyanide transport to mitochondria
          • must be given shortly after exposure
    • note: victims of house fires may have both CO and CN poisoning
  • ATPase inhibitors
    • directly inhibit mitochondrial ATP synthase
      • result
        • ↑ proton gradient
          • no ATP is produced because electron transport stops
    • e.g. oligomycin
  • uncoupling agents
    • “uncouples” ATP production from the proton gradient
    • ↑ permeability of membrane
      • result
        • ↓ proton gradient
        • ↑ O₂, NADH consumption
        • ATP synthesis stops, but electron transport continues
          • produces heat
      • examples
        • 2,4-DNP
        • aspirin/salicylates
          • fevers often occur after aspirin overdose
        • thermogenin in brown fat
          • UCP protein
• generates heat for newborns

Compound	Site of inhibition
CO (carbon monoxide)	Cytochrome c
CN (cyanide)	Cytochrome c
Antimycin	Cytochrome b/c1
Doxorubicin	CoQ
Rotenone (pesticide)	NADH dehydrogenase

Introduction

The electron transport chain (ETC) is a series of protein complexes and electron carriers located in the inner mitochondrial membrane that plays a critical role in cellular respiration. The ETC is responsible for transferring electrons from electron donors, such as NADH and FADH2, to electron acceptors, such as molecular oxygen (O2), in a series of redox reactions.

Types

There are four main protein complexes involved in the electron transport chain, as well as several electron carriers. These include:

1. NADH dehydrogenase complex (Complex I): This complex accepts electrons from NADH and transfers them to ubiquinone (coenzyme Q). It also pumps protons from the mitochondrial matrix to the intermembrane space, contributing to the proton gradient.
2. Succinate dehydrogenase complex (Complex II): This complex accepts electrons from succinate and transfers them to ubiquinone. Unlike Complex I, it does not pump protons across the inner mitochondrial membrane.
3. Cytochrome b-c1 complex (Complex III): This complex accepts electrons from ubiquinone and transfers them to cytochrome c, a soluble electron carrier in the intermembrane space. It also pumps protons from the mitochondrial matrix to the intermembrane space.
4. Cytochrome oxidase complex (Complex IV): This complex accepts electrons from cytochrome c and transfers them to molecular oxygen (O2), which serves as the final electron acceptor. It also pumps protons from the mitochondrial matrix to the intermembrane space.

In addition to these protein complexes, there are several electron carriers that shuttle electrons between the complexes. These include ubiquinone (coenzyme Q), cytochrome c, and cytochrome a/a3. The electron transport chain also requires ATP synthase, which is an enzyme that synthesizes ATP using the energy from the proton gradient generated by the electron transport chain.

Studies

The electron transport chain (ETC) has been extensively studied in the field of biochemistry, and research on this topic has yielded a wealth of information about its mechanisms and regulation. Here are some examples of studies related to the electron transport chain:

1. The discovery of the ETC: The electron transport chain was first discovered by the biochemist David Keilin in the 1920s, through his work on the respiratory pigments of mitochondria. He observed that these pigments, which we now know are cytochromes, are involved in a series of redox reactions that transfer electrons through the mitochondrial membrane.
2. Regulation of the ETC by oxygen: The ETC is regulated by oxygen, which serves as the final electron acceptor. Studies have shown that changes in oxygen levels can affect the activity of the ETC, and that defects in the ETC can lead to a variety of diseases related to oxidative stress, such as Parkinson’s disease.
3. Role of ETC in aging: The electron transport chain has also been implicated in the aging process, as it generates reactive oxygen species (ROS) that can damage cellular components over time. Research has shown that reducing the activity of the ETC can extend the lifespan of model organisms such as worms and flies.
4. Involvement of ETC in metabolic diseases: Dysfunction of the ETC has been implicated in a range of metabolic diseases, including type 2 diabetes and obesity. Studies have shown that defects in Complex I of the ETC can impair insulin secretion and lead to glucose intolerance, while defects in Complex IV can increase the production of ROS and contribute to insulin resistance.
5. Targeting ETC in cancer therapy: The electron transport chain has also emerged as a potential target for cancer therapy. Some cancer cells have an altered metabolism that relies heavily on glycolysis rather than oxidative phosphorylation, a phenomenon known as the Warburg effect. Researchers are exploring ways to target the ETC in cancer cells to selectively kill them while sparing normal cells.

Complications

The electron transport chain (ETC) is a critical process in cellular respiration and energy production, and dysfunction of the ETC can lead to a range of complications. Here are some examples:

1. Mitochondrial diseases: Mitochondrial diseases are a group of disorders caused by mutations in genes involved in mitochondrial function, including those related to the ETC. These disorders can affect multiple organ systems, including the brain, heart, and muscles, and can lead to symptoms such as muscle weakness, seizures, and developmental delays.
2. Oxidative stress: The electron transport chain generates reactive oxygen species (ROS) as a byproduct of its activity, and excessive ROS production can lead to oxidative stress. This can cause damage to cellular components such as DNA, lipids, and proteins, and has been implicated in a range of diseases, including cancer, neurodegenerative disorders, and cardiovascular disease.
3. Metabolic diseases: Dysfunction of the ETC has been linked to a range of metabolic diseases, including type 2 diabetes and obesity. Insulin resistance, which is a hallmark of type 2 diabetes, has been linked to defects in Complex IV of the ETC, which can increase ROS production and impair insulin signaling.
4. Drug toxicity: Some drugs can interfere with the function of the ETC, leading to toxicity. For example, the antipsychotic drug chlorpromazine has been shown to inhibit Complex I of the ETC, leading to mitochondrial dysfunction and oxidative stress.
5. Age-related decline: The electron transport chain has been implicated in the aging process, as it generates ROS that can damage cellular components over time. Age-related declines in mitochondrial function have been linked to a range of age-related diseases, including Alzheimer’s disease and Parkinson’s disease.

Check out USMLE Success Strategy: Personalized Consultation and Study Plan Development.