Phys lecture 8/8/26

Cellular Respiration Overview & Glycolysis

• Definition of Aerobic Respiration: Aerobic respiration is the multi-step metabolic pathway by which cells break down glucose in the presence of oxygen ($O_2$) to produce adenosine triphosphate ($ATP$), carbon dioxide ($CO_2$), and water ($H_2O$).

• Three Primary Systems/Steps of Aerobic Respiration:

  • Glycolysis
  • Citric Acid Cycle (Krebs Cycle)
  • Electron Transport Chain (ETC) and Oxidative Phosphorylation

• Glycolysis Overview & Location:

  • Takes place entirely within the cytoplasm (cytosol) of the cell.
  • Starts with $1$ single molecule of glucose ($C_6H_{12}O_6$).
  • Does not require oxygen directly, making glycolysis itself an anaerobic process when evaluated in isolation.
  • Glucose stored in the cytoplasm can originate directly from cellular uptake or from the breakdown of stored glycogen.

• Energy Investment & Production Steps of Glycolysis:

  • Energy Deficit (Investment Phase): The process initially costs the cell $2$ molecules of $ATP$ to phosphorylate glucose and break it down into intermediate triose sugars.
  • Energy Payoff Phase: Glycolysis subsequently generates $4$ molecules of $ATP$ via substrate-level phosphorylation.
  • Net $ATP$ Yield:     $\text{Net } ATP = 4\text{ } ATP\text{ (produced)} - 2\text{ } ATP\text{ (invested)} = 2\text{ } ATP$
  • Coenzyme Reduction: Glycolysis reduces $2$ molecules of $NAD^+$ to form $2$ molecules of $NADH$ by picking up hydrogen ions ($H^+$) and high-energy electrons.
  • End Products: Produces $2$ molecules of pyruvic acid (also referred to interchangeably as pyruvate).

• Fate of Pyruvic Acid (Pyruvate):

  • Aerobic Environment (Oxygen Present): Pyruvic acid is transported across the outer and inner mitochondrial membranes into the mitochondrial matrix to be converted into acetyl coenzyme A (acetyl CoA).
  • Anaerobic Environment (Oxygen Absent or Deficient):
  • Oxygen availability becomes the limiting factor.
  • The enzyme lactate dehydrogenase catalyzes a reaction where the $2$ $NADH$ molecules produced during glycolysis transfer their hydrogen atoms and electrons back to the $2$ pyruvic acid molecules.
  • Gaining these hydrogens increases acidity, converting pyruvic acid into lactic acid (lactate).
  • This conversion oxidizes $NADH$ back to $NAD^+$ so that glycolysis can continue regenerating a minimal amount of $ATP$ ($2\text{ } ATP$ net) under anaerobic conditions.

• The Cori Cycle (Lactic Acid Metabolism):

  • Lactic acid produced in hypoxic skeletal muscle tissue diffuses into the bloodstream and is transported to the liver.
  • In the liver, the Cori Cycle converts lactic acid back into pyruvic acid (producing $NADH$ in the process).
  • The liver then converts pyruvic acid back into glucose via gluconeogenesis.
  • Re-synthesized glucose is released into the blood to be utilized by skeletal muscle or other tissues.

The Transition Step & The Krebs Cycle (Citric Acid Cycle)

• The Transition / Intermediate Step:

  • Occurs as pyruvic acid moves from the cytoplasm into the mitochondrial matrix.
  • Enzymatic Conversion: Each $3$-carbon pyruvic acid molecule undergoes oxidative decarboxylation to form a $2$-carbon acetyl CoA molecule.
  • Transitional Coenzyme Yield:
  • For every $1$ pyruvic acid converted to acetyl CoA, $1$ molecule of $NADH$ is produced.
  • Because $1$ glucose molecule produces $2$ pyruvic acid molecules, the net yield of the transition step per glucose molecule is $2$ molecules of $NADH$ and $2$ molecules of acetyl CoA.

• Krebs Cycle (Citric Acid Cycle) Overview:

  • Takes place inside the mitochondrial matrix.
  • Driven by the entry of acetyl CoA.
  • Runs $2$ full turns per original glucose molecule (since $1$ glucose yields $2$ acetyl CoA).

• Chemical Yield of the Krebs Cycle:

  • Per Single Molecule of Acetyl CoA (1 Turn):
  • $3$ $NADH$
  • $1$ $FADH_2$
  • $1$ $ATP$ (derived via guanosine triphosphate / $GTP$ synthesis intermediate)
  • $2$ $CO_2$ (carbon dioxide molecules)
  • Per Molecule of Glucose (2 Turns):
  • $6$ $NADH$
  • $2$ $FADH_2$
  • $2$ $ATP$
  • $4$ $CO_2$

• Fate of Carbon Dioxide ($CO_2$):

  • $CO_2$ generated in the Krebs cycle diffuses out of the mitochondrial matrix into the cytoplasm, moves into the bloodstream, travels to the lungs, and is expired.
  • It can also be utilized elsewhere in the body for anabolic chemical reactions.

• Keto Acids vs. Ketone Bodies in Metabolism:

  • Intermediates of the Krebs cycle include organic keto acids such as $\alpha$-ketoglutaric acid, fumaric acid, and oxaloacetic acid.
  • Keto Acids: Organic acids containing a functional carboxylic acid group and a ketone group. They originate directly from the deamination of amino acids (amino acids that have lost their amine group, $-NH_2$). Adding an amine group back to a keto acid synthesizes an amino acid.
  • Ketone Bodies: Acetoacetate, $\beta$-hydroxybutyrate, and acetone produced during excessive fatty acid breakdown in the liver. Keto acids and ketone bodies are chemically distinct entities.
  • Dietary Importance: Adequate dietary consumption of amino acids is necessary to maintain pool levels of keto acid intermediates in the Krebs cycle. Amino acid deficiencies impair Krebs cycle turnover, directly decreasing energy production and systemic physiological performance.

Electron Transport Chain & Oxidative Phosphorylation

• Location & Architecture:

  • Located on the inner mitochondrial membrane (folded into cristae).
  • Consists of a series of membrane-bound protein complexes and electron pumps.

• Function of Reduced Coenzymes ($NADH$ and $FADH_2$):

  • Water-soluble vitamins serve as precursors to coenzymes $NAD^+$ (niacin/vitamin B3) and $FAD$ (riboflavin/vitamin B2).
  • $NADH$ and $FADH_2$ act as high-energy electron shuttles that deliver electrons and hydrogen ions ($H^+$) harvested during glycolysis, the transition step, and the Krebs cycle to the ETC protein complexes.

• Mechanistic Sequence of Oxidative Phosphorylation:

  1. Oxidation of Coenzymes: $NADH$ and $FADH_2$ release their high-energy electrons to the ETC protein complexes, oxidizing them back to $NAD^+$ and $FAD$.
  2. Proton Pumping: The transfer of electrons through the protein complexes provides energy to actively pump hydrogen ions ($H^+$) across the inner mitochondrial membrane from the mitochondrial matrix into the intermembrane space.
  3. Establishment of Electrochemical Gradient: Proton pumping creates a high concentration of $H^+$ inside the intermembrane space relative to the low concentration in the matrix.
  4. Proton Diffusion through ATP Synthase: Driven by simple diffusion principles (movement down a concentration gradient from high to low concentration), $H^+$ ions pass back into the matrix through a specialized trans-membrane protein enzyme called $ATP$ synthase.
  5. Phosphorylation: The physical passage of $H^+$ down its electrochemical gradient activates $ATP$ synthase, driving the mechanical phosphorylation of adenosine diphosphate ($ADP$) and inorganic phosphate ($P_i$) into $ATP$:      $ADP + P_i \rightarrow ATP$

• **Clarification of