Podcast #3-Cellular energy metabolism and the mitochondria

 

In this podcast I cover basic energy metabolism within the cell, with particular emphasis on how the mitochondria play a role.  I also discuss the NAD+/NADH and things that lead to the age-related decline in the NAD+ pool and how circadian rhythms fit in to the picture.  Below are the pictures and outline for this podcast to follow along with.

Image result for nad glycolysis

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  • Energy metabolism in the cytosol
    • What is a redox pair?
      • NAD+/NADH, FAD/FADH2
    • Glycolysis yields pyruvate or lactate, 2 ATP and 2 NADH
      • Dependent on the rate of energy production
      • Pyruvate & NADH are shuttled in to the mitochondria
      • Lack of O2 or mitochondria leads to lactate accumulation
    • Pyruvate and lactate are only metabolized in the mitochondria

Image result for energy metabolism mitochondria

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  • Energy metabolisms in the mitochondria (~30 ATP from glucose, >100 ATP from fatty acids
    • Pyruvate/lactate converted to Acetyl CoA
    • The citric acid cycle(Krebs cycle, tricarboxylic acid cycle, TCA cycle)
      • Uses NAD+, NADH enters ETC
    • Beta oxidation of fatty acids
      • Acetyl CoA Feeds in to the TCA cycle
      • FADH2 enters the ETC
    • Electron transport chain(ETC)
      • NADH and succinate generated via TCA cycle

 

  • System-wide energy metabolism
    • During exercise, working muscles make lactate to maintain high cytosolic NAD+/NADH ratio
    • Lactate is either:
      • Transported to the mitochondria of that muscle cell, converted to pyruvate then Acetyl CoA to enter the TCA
      • Kicked out of that muscle cell and transported to another local muscle cell to enter its mitochondria
      • Enters the circulation and Metabolized by the brain, heart, and other muscles
      • Converted to glucose in the liver, kidney, and gut
    • Lactate can form due to high energy demand or high glucose supply

Image result for NAD+ synthesis

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  1. Factors affecting NAD+ availability
    1. Synthesis occurs via de novo production from tryptophan as well as the salvage pathway
    2. PARP1(Poly [ADP-ribose] polymerase 1)-DNA repair
      1. NAD to NAM
    3. CD38-PM anchored enzyme, involved in inflammation, induced by endotoxin
      1. NAD to NAADP
    4. Sirtuins (1-7)-DNA repair, Epigenetics(Deacetylase), cell metabolism, increase NAD+ biosynthesis.  Converts NAD to NAM.  SIRT3-5 in mitochondria
      1. Activated by fasting
      2. Replenish NAD+ levels via the salvage pathway
      3. Regulate NAMPT(Nicotinamide phosphoribosyltransferase) (SIRT1 cytoplasm, nucleus)-NAM to NMN
    5. Loss of NAD+ from any of these pathways decreases energy metabolism(We need NAD+/NADH and these pathways form something else)
      1. Fasting induces SIRT1 to ramp up the salvage pathway and increases the NAD+/NADH because you’re not using energy

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