Cellular energetics

Metabolism

• Metabolism is the sum of all chemical reactions in the body.

Exergonic and Endergonic Reactions

• Exergonic reactions release energy, have a negative ΔG, and are spontaneous. They are catabolic reactions that break down molecules.
• Endergonic reactions require energy, have a positive ΔG, and are non-spontaneous. They are anabolic reactions that build up molecules.

Energy Coupling

• Endergonic reactions are coupled to exergonic reactions to drive them forward.

ATP Hydrolysis

• ATP is the major energy currency of cells.
• ATP hydrolysis is an exergonic reaction that releases energy: ATP → ADP + Pi, ΔG = -7.3 kcal/mol.
• Cells regenerate ATP from ADP + Pi through cellular respiration.

Cellular Respiration

• Cellular respiration is the process of regenerating ATP from ADP + Pi.
• Aerobic cellular respiration requires oxygen and involves the complete oxidation of glucose to CO2 and the reduction of oxygen to H2O.
• The chemical equation for aerobic cellular respiration is: C6H12O6 + 6O2 → 6H2O + 6CO2.
• Cellular respiration requires both the cytosol and mitochondria.

Mitochondria

• Mitochondria are organelles that are responsible for cellular respiration.
• Mitochondria originated from free-living bacteria through endosymbiosis.

Stages of Aerobic Cellular Respiration

• There are four stages of aerobic cellular respiration:
  • Glycolysis: Occurs in the cytosol and breaks down glucose into pyruvate.
  • Oxidation of Pyruvate: Occurs in the mitochondrial matrix and converts pyruvate into acetyl-CoA.
  • TCA Cycle (Krebs Cycle): Occurs in the mitochondrial matrix and oxidizes acetyl-CoA to CO2, generating electron carriers.
  • Chemiosmosis, Oxidative Phosphorylation, and Electron Transport Chain: Occurs in the mitochondrial matrix, intermembrane space, and inner mitochondrial membrane, and uses electron carriers to generate ATP.

Comparing Substrate-Level and Oxidative Phosphorylation

• Substrate-level phosphorylation directly transfers a phosphate group from a substrate to ADP, generating ATP.
• Oxidative phosphorylation uses the electron transport chain and oxygen to generate ATP. It is the main source of ATP during aerobic respiration.

Electron Carriers

• NAD+ (Nicotinamide Adenine Dinucleotide) and FAD (Flavin Adenine Dinucleotide) are electron carriers involved in cellular respiration.
• NAD+ and FAD are oxidized forms that do not carry electrons.
• NADH and FADH2 are reduced forms that carry two electrons each.

Glycolysis

• Glycolysis has two phases:
  • Energy-requiring phase: Requires 2 ATP per glucose.
  • Energy-yielding phase: Produces 4 ATP per glucose.

Outputs of Glycolysis

• Per glucose molecule, glycolysis produces:
  • 2 NADH (4 electrons)
  • 2 pyruvate
  • 4 ATP (2 net) by substrate-level phosphorylation.

Anaerobic Conditions

• If there is no oxygen, cells can only regenerate ATP by glycolysis.
• This leads to an increase in glucose uptake (Pasteur effect).
• Fermentation is used to oxidize NADH to NAD+ and regenerate ATP in anaerobic conditions.

ADP Levels and Respiration

• Low levels of ADP decrease the rate of respiration.
• High levels of ADP increase the rate of respiration.

Uncouplers

• Uncouplers inhibit ATP synthesis by separating the proton-motive force across the inner mitochondrial membrane from ATP synthase.
• Examples include chemical uncouplers (DNP) and natural substances like thermogenin.

Metabolic Blocks

• Metabolic blocks prevent electron flow through the electron transport chain, disrupting the proton gradient and reducing ATP generation.
• Examples include cyanide, rotenone, malonate, antimycin-a, and oligomycin.

Alternative Fuels

• Cells can utilize other organic compounds to regenerate ATP in the absence of glucose.
• β-oxidation: Uses fatty acids for mitochondrial respiration.
• Gluconeogenesis: Produces glucose from sources other than glycogen.
• Different cell types have different preferences for fuel sources. For example, neurons, erythrocytes, and kidney medullar cells primarily use glucose, while cardiomyocytes preferentially use fatty acids.

Metabolism Overview

• Metabolism: Summation of all chemical reactions within an organism
• Complex human metabolic map
• Reactions can be exergonic or endergonic
  • Exergonic reactions release energy (downhill) and have a negative ΔG
  • Endergonic reactions require energy (uphill) and have a positive ΔG
  • Catabolic reactions are exergonic and break down molecules
  • Anabolic reactions are endergonic and build up molecules

Energy Coupling

• Endergonic reactions are coupled to exergonic reactions
• Theoretically, any endergonic reaction can be coupled to any exergonic reaction
• ATP hydrolysis is the most common exergonic coupling reaction

ATP Hydrolysis

• ATP: Primary energy currency of cells
• ATP hydrolysis: ATP  ADP + Pi; releases -7.3 kcal/mol of energy
• Cells regenerate ATP from ADP + Pi through cellular respiration
• Average human regenerates about 100 moles of ATP per day (~6x1020 ATP/second)

Cellular Respiration

• Chemical equation: C6H12O6 + 6O2  6H2O + 6CO2
• Glucose is oxidized to CO2 and oxygen is reduced to H2O
• Requires both cytosol and mitochondria in eukaryotic cells

Mitochondrion

• Origin: Endosymbiotic process: Mitochondria evolved from free-living bacteria that were engulfed by an early eukaryotic cell
• Some mitochondrial genes migrated to the nucleus.

Aerobic Cellular Respiration

• Obligate aerobes, facultative aerobes, and facultative anaerobes undergo aerobic respiration
• Four spatially separated reactions:
  • Glycolysis: Cytosol
  • Oxidation of pyruvate: Mitochondrial matrix
  • TCA cycle: Mitochondrial matrix
  • Chemiosmosis, Oxidative phosphorylation, and electron transport chain: Mitochondrial matrix, intermembrane space, and inner mitochondrial membrane

Comparing Substrate-Level & Oxidative Phosphorylation

• Substrate-level phosphorylation: Directly transfers a phosphate group from a substrate molecule to ADP
• Oxidative phosphorylation: Utilizes electron transport chain and oxygen to generate ATP; most ATP produced during aerobic respiration

Electron Carriers

• NAD+ (Nicotinamide Adenine Dinucleotide) and FAD (Flavin Adenine Dinucleotide)
• NAD+ and FAD are oxidized forms without electrons; reduced forms carry 2 electrons each
  • NAD+  NADH + H+
  • FAD  FADH2

Glycolysis

• Two phases:
  • Energy-requiring phase: Requires 2 ATP per glucose
  • Energy-yielding phase: Produces 4 ATP per glucose
• By the end of glycolysis:
  • 2 NADH (4 e-)
  • 2 pyruvate
  • 4 ATP (2 net) produced through substrate-level phosphorylation

Without Oxygen

• Cells only regenerate ATP through glycolysis
• Increased glucose uptake (Pasteur effect): Shift from slow aerobic to rapid anaerobic glucose consumption
• Fermentation: NADH is oxidized to NAD+ to continue glucose breakdown
  • Lactic acid accumulates in muscles

ADP Levels & Respiratory Rate

• Endogenous ADP is depleted by ATP formation
• Low ADP levels decrease respiratory rate; high ADP levels increase respiratory rate

Uncouplers

• Separate proton-motive force from ATP synthesis, inhibiting ATP generation
• Chemical uncouplers (e.g., 2,4-dinitrophenol) and natural substances (e.g., thermogenin)

Metabolic Blocks

• Prevent electron flow through the ETC
• Disrupt proton gradient, reducing ATP production
• Examples: Cyanide, rotenone, malonate, antimycin-A, oligomycin

Alternative Fuels

• Most cells prefer glucose for respiration
• Cells can metabolize other organic compounds in absence of glucose:
  • β-oxidation: Use of fatty acids for mitochondrial respiration
  • Gluconeogenesis: Production of glucose from sources other than glycogen
• Some cells (neurons, erythrocytes, kidney medulla cells) use only glucose, while others may preferentially use fatty acids (e.g., cardiomyocytes)

2,4-Dinitrophenol (DNP)

• Chemical uncoupler that dissipates proton gradient across the inner mitochondrial membrane, reducing ATP synthesis and increasing heat generation

Thermogenin

• Proton carrier protein found in brown fat mitochondria
• Transports protons across mitochondrial membrane without ATP synthase, generating heat instead of ATP
• More common in children than adults

Test your knowledge on metabolism, including exergonic and endergonic reactions, energy coupling, and ATP hydrolysis. This quiz covers the fundamental concepts necessary for understanding cellular respiration and the energy processes in living organisms.