Cellular Energy Metabolism and Regulation

Posted on Oct 14, 2025 in Biology

Blood Glucose Regulation and Signaling

Specificity: Only cells with the appropriate receptor respond to a signal. Sensitivity: Signals are amplified, allowing them to work effectively at low concentrations.

Hormone Classification and Receptors

Hormones are categorized into three structural groups:

  • Derivatives of Amino Acids (e.g., Epinephrine): Mostly not lipid soluble; bind to receptors on the surface of the target cell.
  • Proteins (e.g., Insulin and Glucagon): Not lipid soluble; bind to receptors on the surface of the target cell.
  • Steroids (e.g., Cortisol): Lipid soluble; often bind to receptors inside the target cell.

Receptors are specific to hormones based on location, shape, weak bonds, and binding site. Kinases add phosphate groups (phosphorylation), which changes protein shape and functionality. The signal transduction pathway, crucial for epinephrine function, happens rapidly.

Negative Feedback Loops

Negative feedback loops maintain homeostasis:

  1. Regulated variable increases.
  2. Detector (afferent pathway: hormones/nerves) increases.
  3. Integrator increases.
  4. Response (efferent pathway: hormones, nerves) increases.
  5. Regulated variable decreases.

Insulin Action

Insulin is secreted by cells in the pancreas when blood glucose levels are too high. It travels through the bloodstream and binds to receptors on target cells. These cells respond by:

  • Increasing glucose uptake and processing.
  • Synthesizing glycogen.

This collective action decreases blood glucose levels. Insulin alters the endomembrane pathway to increase plasma membrane GLUT4 transporters. This process involves many steps due to the need for sensitivity and amplification.

Related Membrane Processes: Endocytosis is the process of absorbing bits of membrane; Exocytosis is the process of merging membrane vesicles back to the plasma membrane.

Thermodynamics and Gibbs Free Energy

Equilibrium is the ratio of chemical concentrations when the net change in concentration equals zero. Thermodynamics, the relationship between heat and other forms of energy, dictates that cells obey the laws of physics and chemistry.

Laws of Thermodynamics

  • First Law: Energy cannot be created or destroyed; it can only be transferred and transformed.
  • Second Law: Systems tend toward the most stable, lowest free energy state. Entropy always increases in an isolated system.

Entropy (S): Represents less stored, clustered, and patterned energy. Entropy increases (ΔS is positive) when products are less ordered than reactants (e.g., dye diffusing in water). A favorable reaction involves a lack of potential energy (P.E.) in bonds; less P.E. means the reaction is exergonic. Weaker, equally shared bonds typically indicate high P.E.

Gibbs Free Energy (G)

Gibbs Free Energy (G) determines whether a reaction will occur spontaneously: ΔG = ΔH – TΔS.

  • If ΔG < 0: The reaction is exergonic (energy releasing) and spontaneous.
  • If ΔG = 0: The reaction is at equilibrium.
  • If ΔG > 0: The reaction is endergonic (requires energy, not favorable) and nonspontaneous.

Enthalpy (ΔH):

  • Exothermic reactions release heat (ΔH is negative).
  • If ΔH is positive, products have more potential energy than reactants.

Under standard conditions (ΔG°), reactions proceed forward without energy input when ΔG° is negative (exergonic). If ΔG° is positive, the reaction requires energy (endergonic). Temperature (T) is measured in Kelvins. Phase changes, like ice melting, depend on temperature, as both ΔH° and ΔS° are positive (Solid → Liquid → Gas represents increasing disorder).

The relationship between standard free energy and the equilibrium constant (Keq) is given by: ΔG° = -RTln(Keq). If Keq is greater than 1, ΔG° is negative, and products are favored.

Enzyme Function and Regulation

Enzyme binding to a substrate changes the enzyme’s shape by altering bonds and tertiary structure. This process, known as “induced fit,” reorients and binds substrates tighter to the active site.

ATP holds significant potential energy due to the strong repulsion between its highly negatively charged phosphate groups.

Factors Determining Enzyme Reaction Rate

The rate of an enzyme-catalyzed reaction is determined by:

  1. Enzyme turnover rate (Kcat) and enzyme kinetics.
  2. Environmental conditions (e.g., temperature, pH; enzymes from different organisms may function best at different temperatures).
  3. Non-covalent regulation:
    • Competitive/Non-competitive Inhibition: A regulatory molecule blocks substrates from the enzyme’s active site (competitive) or binds elsewhere to change the active site shape (non-competitive).
    • Allosteric Regulation (Activation/Inhibition): A regulatory molecule activates or deactivates the enzyme’s active site noncompetitively.
  4. Covalent modifications of the enzyme (e.g., phosphorylation).

Glycolysis: Breaking Down Glucose

Glycolysis breaks down glucose into useful energy. ATP synthesis occurs through an exergonic reaction coupled to an endergonic reaction.

Phases of Glycolysis

  1. Preparatory Phase (Energy Investment): Energy from ATP must be added first to release the energy stored in glucose. Two ATP molecules are consumed, producing a glucose molecule with two phosphate groups. These phosphate groups destabilize glucose, preparing it for chemical breakdown and lending potential energy from their negative charges.
  2. Payoff Phase (Energy Generation): This phase forms four ATP molecules and two NADH molecules, resulting in a net gain of two ATP and two molecules of pyruvate.

Pyruvate Processing and the Krebs Cycle

Pyruvate, the end product of glycolysis, is transported into the mitochondrion and converted to Acetyl CoA. This conversion (Pyruvate Processing) also transfers electrons to NAD⁺, storing energy as NADH.

The Krebs Cycle (or Citric Acid Cycle) consists of nine enzyme-catalyzed reactions divided into three stages:

  1. Acetyl CoA binds to a four-carbon molecule (oxaloacetate), producing a six-carbon molecule (citrate).
  2. Two carbons are removed as carbon dioxide (CO₂).
  3. The four-carbon starting material (oxaloacetate) is regenerated.

The Krebs Cycle generates ATP and many energized electrons (in the form of FADH₂ and NADH) for the Electron Transport Chain (ETC).

Summary of Aerobic Respiration Flow

1 Glucose → Glycolysis (NADH + ATP → Pyruvate) → Pyruvate Processing (NADH + CO₂ → 2 Acetyl CoA) → Citric Acid Cycle (ATP + NADH + FADH₂) → Electron Transport and Oxidative Phosphorylation (O₂ in, H₂O + ATP out).

The overall reaction for glycolysis is: C₆H₁₂O₆ + 2 ATP + 4 ADP + 4 Pi + 2 NAD⁺ → 2 Pyruvate + 4 ATP + 2 Pi + 2 NADH.

Anaerobic Conditions and NAD+ Replenishment

NADH and FADH₂ are high-energy electron carriers used to transport electrons to the ETC. If oxygen (the final electron acceptor in the ETC) is absent, glycolysis stops because NAD⁺ cannot be replenished, potentially leading to cell death.

Ways to replenish NAD⁺:

  1. Aerobic Respiration: NADH indirectly transfers electrons to oxygen via the ETC. (Yields ~29 ATP).
  2. Fermentation (Anaerobic): If oxygen is not present, fermentation recycles NADH + H⁺ back to NAD⁺ so glycolysis can continue. (Yields 2 ATP).

Fermentation produces lactate or ethanol/small organic molecules and synthesizes ATP only by substrate-level phosphorylation. Cellular Respiration (aerobic) yields approximately 30 ATP, requires O₂, produces CO₂ and H₂O, occurs in mitochondria, and synthesizes ATP by oxidative phosphorylation (chemiosmosis). The standard free energy change (ΔG°) for cellular respiration is approximately -686 kcal/mol.

Glycolysis Regulation

The first committed step of glycolysis is catalyzed by Phosphofructokinase (PFK). ATP acts as both a substrate and an allosteric inhibitor of PFK, demonstrating feedback inhibition. ATP in glycolysis is synthesized by substrate-level phosphorylation. Ultimately, all carbons in glucose are completely oxidized during aerobic respiration, and ATP is produced via chemiosmosis driven by the proton motive force, which requires a membrane.

Metabolic Adaptation in Naked Mole Rats

The regulation of Phosphofructokinase (PFK) is critical because the reaction it catalyzes is irreversible. PFK is the rate-limiting step in glucose metabolism and is tightly regulated, subject to feedback inhibition via allosteric binding of ATP and low pH.

Naked mole rats exhibit an alternative metabolism, bypassing the PFK regulatory step, especially when oxygen-deprived. Their mechanisms include:

  • Oxygen-deprived mole rats express the GLUT5 gene, responsible for fructose transport across mammalian cellular membranes.
  • GLUT5 is expressed at high levels in all examined tissues (including brain, heart, liver, and lung).
  • Under near-anaerobic conditions, their heart and brain cells metabolize fructose instead of glucose to generate energy.

This metabolic rewiring allows them to use a pathway that metabolizes fructose to lactate, effectively bypassing the metabolic block imposed by PFK regulation during low oxygen availability.

Endosymbiosis Theory: Mitochondria and Chloroplasts

The Endosymbiotic Theory proposes that mitochondria and chloroplasts evolved from prokaryotes that were engulfed by host cells, establishing a symbiotic existence within them. Mitochondria are found in nearly all eukaryotic cells (plants, animals, and fungi).

Evidence Supporting Endosymbiosis

  • They possess a double membrane.
  • Alpha proteobacteria are similar in size to mitochondria.
  • Both organelles have their own DNA and ribosomes, organized as a circular chromosome.
  • Chloroplasts divide by fission, similar to cyanobacteria.
  • They possess unique membrane proteins and lipids.
  • They reproduce independently and can only be generated from existing organelles.
  • Phylogenetic evidence supports the endosymbiotic origin of mitochondria.

Secondary Endosymbiosis occurs when a living cell engulfs another eukaryote that has already undergone primary endosymbiosis.

In the primary relationship, the host cell gains ATP, while the engulfed prokaryote (proto-mitochondrion) gains shelter, sugar, and proteins. In some cases, the host loses its feeding apparatus and becomes an autotroph, while the ingested algae lose structures like flagella, cytoskeleton, endomembrane system, mitochondria, and Golgi apparatus.

Regulation of the Citric Acid Cycle (CAC)

The Citric Acid Cycle (CAC) occurs in the mitochondrial matrix in eukaryotes and in the cytosol in prokaryotes.

Pyruvate, formed during glycolysis in the cytosol, is imported into the mitochondria. It is then processed into Acetyl CoA, the substrate that enters the CAC. This processing involves the loss of carbon (as CO₂), the reduction of NAD⁺ to NADH, and the binding of Coenzyme A to form Acetyl CoA. Two pyruvate molecules are formed per glucose molecule.

Pyruvate Dehydrogenase (PDH) Regulation

The Pyruvate Dehydrogenase (PDH) complex oxidizes pyruvate to Acetyl CoA, acting as a gatekeeper for aerobic respiration. Its activity is tightly regulated by phosphorylation (feedback inhibition):

  • Stimulation (Low Energy): Elevated levels of NAD⁺ and CoA indicate low ATP supplies and stimulate PDH activity.
  • Inhibition (High Energy): Elevated levels of Acetyl CoA and NADH indicate high ATP supplies and inhibit PDH activity (via phosphorylation). When PDH is phosphorylated, it stops.

Overall, PDH is inhibited by ATP, Acetyl CoA, and NADH, and accelerated by NAD⁺, CoA, and AMP. Since the CAC is aerobic, the absence of O₂ leads to a buildup of NADH and FADH₂.

Carbon Fate and Energy Yield

Carbons entering the CAC can be classified:

  • “Lifers” (Core Carbons): These are core carbons bound to carboxyl carbons, remaining in the cycle.
  • “Carboxyls”: These are part of carboxyl groups and are oxidized to CO₂ within one or two full cycles. Carboxyl carbons become progressively more oxidized.

Per glucose molecule, the CAC yields 6 NADH, 2 FADH₂, and 2 ATP (or GTP). The cycle is regulated by feedback inhibition, with the first step regulated by ATP, and steps 3 and 4 regulated by NADH and ATP.

Glucose stores chemical energy in less polar carbon bonds, which is converted into NADH, FADH₂, and ATP. Theoretical ATP yield is often calculated as 2.5 ATP per NADH and 1.5 ATP per FADH₂. The total theoretical yield (32 ATP) is often reduced to approximately 29 ATP because active transport is required to move pyruvate into the mitochondria.

Electron Transport Chain (ETC) and ATP Synthesis

The ETC occurs in the inner mitochondrial membrane of eukaryotes or the plasma membrane of prokaryotes. Reducing agents, NADH and FADH₂, donate high-energy electrons.

Electron Flow and Proton Pumping

The ETC consists of four transmembrane protein complexes containing metal ions that facilitate electron movement. Electron movement involves a series of oxidation-reduction (redox) reactions: molecules donating electrons become oxidized, and receiving molecules become reduced. Electrons spontaneously pass from molecules with a lower affinity for electrons to those with a higher affinity.

Electrons from NADH enter Complex I, where their free energy declines. This energy release is coupled to pumping protons (H⁺) from the mitochondrial matrix into the intermembrane space. FADH₂ enters the chain later (at Complex II). The resulting proton gradient drives the synthesis of the vast majority of ATP produced by aerobic cellular respiration.

Chemiosmosis and ATP Synthase

ATP Synthase is the enzyme that synthesizes ATP via chemiosmosis. It uses the energy released by the dissipation of the proton gradient to drive synthesis, converting the flow of protons from an area of high H⁺ concentration and positive charge (intermembrane space) to an area of low H⁺ concentration (matrix). Approximately 3 H⁺ are required per ATP produced.

Oxidative Phosphorylation is ATP production driven by a proton motive force generated by the redox reactions of the ETC, which oxidizes high-energy electron donors. The ultimate electron acceptor is Oxygen (O₂).

Efficiency and Uncoupling

A higher H⁺ concentration leads to a greater membrane potential and potentially more ATP synthesis. However, Uncoupling Proteins (UCPs) allow protons to pass across the inner mitochondrial membrane without going through ATP synthase. This bypass dissipates the proton motive force, releasing the energy as heat (thermoregulation).

Prokaryotes utilize a gradient between the cytosol and the outside world for oxidative phosphorylation, whereas mitochondria maintain a more controlled and polarized membrane environment.

Photosynthesis: Capturing Light Energy

The overall simplified reaction for photosynthesis is: 3 CO₂ + 3 H₂O + Energy → Carbohydrate + 3 O₂.

Photosynthesis harnesses light energy captured by chloroplast pigments to split water, generating an electron source. These electrons power the chlorophyll electron transport chain to produce ATP and reduce NADP⁺ to NADPH, which subsequently powers the Calvin-Benson cycle to produce sugars.

In organisms without stomata, CO₂ must diffuse through water and cell membranes. Photosynthetic activity can be measured using primary productivity measurements or carbon flux towers.

Light Absorption and Electron Excitation

Light is characterized by wavelengths and energy (c = λv). Pigments are molecules that reflect specific wavelengths (e.g., violet, blue, yellow, and red are often reflected most). When electrons absorb light, they become excited to a higher energy state. The excited electron can return to a lower state via several mechanisms:

  • Fluorescence/Heat: The electron drops back down, releasing energy as light or heat.
  • Resonance Energy Transfer: Energy is transferred to a nearby pigment molecule (e.g., chlorophyll oxidized, reaction center reduced).
  • Reduction/Oxidation: The electron is transferred to a new compound.

Photosystems I and II in Thylakoid Membranes

Reaction centers are surrounded by antenna complexes, which house chlorophyll and carotenoid molecules that funnel light energy to the reaction centers.

Photosystem II (PSII)

PSII oxidizes the reaction center (P680) and reduces pheophytin and the cytochrome complex. Electrons are replaced by the splitting of water (photolysis). Splitting water generates a source of electrons and protons (H⁺), which accumulate in the thylakoid lumen. This proton accumulation drives ATP production via the proton-motive force.

Non-Cyclic Electron Flow

In non-cyclic flow, electrons move sequentially from Photosystem II (P680) to Photosystem I (P700). Photosystem I (PSI) ultimately reduces NADP⁺ to NADPH. The observation that O₂ production is greater when both 700nm and 680nm wavelengths are used together (the enhancement effect) suggests that the photosystems cooperate.

Cyclic Electron Flow (Photosystem I)

Photosystem I can operate in a cyclic flow, driving cyclic photophosphorylation. The excited electron is sent to ferredoxin, which reduces plastoquinone, which then reduces the cytochrome complex. This flow produces only ATP via the proton-motive force and occurs when the cell is short on electrons or needs ATP but not NADPH or O₂.

The ETC pumps H⁺ into the lumen. The ultimate destination of electrons in the light reactions is NADPH. Both ATP and NADPH are then used to power the Calvin Cycle.

The Calvin Cycle (Carbon Fixation Reactions)

The carbon reactions (or Calvin-Benson Cycle) fix carbon from CO₂ into a reduced carbon compound. This cycle is powered by the ATP and NADPH generated during the light reactions.

Three Phases of the Calvin Cycle (for 3 CO₂ molecules)

  1. Fixation of CO₂: 3 RuBP + 3 CO₂ → 6 3-PGA. Carbon dioxide binds to the five-carbon molecule Ribulose-1,5-bisphosphate (RuBP), catalyzed by Rubisco, producing two molecules of 3-Phosphoglycerate (3-PGA), a three-carbon molecule. (No ATP or NADPH needed here).
  2. Reduction of 3-PGA to G3P: 6 3-PGA + 6 ATP + 6 NADPH → 6 G3P. ATP and NADPH are required to push these endergonic reactions forward. 3-PGA is reduced to Glyceraldehyde 3-Phosphate (G3P), the primary product of the cycle.
  3. Regeneration of RuBP: 5 G3P + 3 ATP → 3 RuBP. One G3P molecule is shunted off to produce sugars, while the remaining five G3P molecules enter the regeneration phase. Three ATP molecules are needed to regenerate the three RuBP molecules. G3P has higher potential energy than 3-PGA.

The Role of Rubisco and Photorespiration

Rubisco (Ribulose-1,5-bisphosphate carboxylase/oxygenase) coordinates the binding of RuBP and CO₂. However, Rubisco is not substrate-specific and will bind both CO₂ and O₂ to RuBP. This inefficiency leads to photorespiration:

  • RuBP + CO₂ → Two 3-Phosphoglycerate (efficient photosynthesis).
  • RuBP + O₂ → One 3-Phosphoglycerate + One 2-Phosphoglycerate (requires ATP to process to CO₂).

Photorespiration is inefficient, slow, wastes energy (does not produce ATP or NADH), and decreases sugar synthesis.

High sugar concentrations in chloroplasts can inhibit both light reaction processes and the Calvin Cycle, slowing carbon assimilation until conditions change.

C4 and CAM Photosynthetic Adaptations

The light reactions produce ATP and NADPH, which the carbon reactions consume. Water evaporation raises turgor pressure but lowers xylem pressure.

C4 Plants

C4 plants avoid photorespiration by using PEP Carboxylase instead of Rubisco for the initial fixation of carbon. PEP Carboxylase has a much higher affinity for CO₂ than Rubisco. This adaptation is advantageous in environments with low CO₂ concentrations and dry climates. In dry soil, C4 plants keep stomata closed during the day to conserve water.

CAM Metabolism

CAM (Crassulacean Acid Metabolism) plants temporally separate carbon fixation. They open stomata at night to fix CO₂ into a C₄ compound, which is stored. During the day, the stomata close, and the stored C₄ compound is broken down to release CO₂ for the Calvin Cycle. This strategy avoids photorespiration by eliminating the need to open stomata during the hot daytime, though it is less efficient and results in slower growth due to limited CO₂ storage capacity.

Principles of Thermoregulation

Thermoregulation describes how organisms maintain body temperature:

  • Endotherm: Relies on internal metabolic heat generation.
  • Ectotherm: Relies on external heat sources.
  • Poikilotherm: Internal temperature matches the external environment.
  • Homeotherm: Regulates a constant internal temperature.

Mammals and birds are typically endothermic homeotherms, while most fish and insects are ectothermic poikilotherms. Some fish exhibit partial homeothermy by generating heat through movement. Notably, naked mole rats have lost the ability to be homeotherms.

Metabolic Rate and Heat Generation

Endotherms maintain a higher metabolic rate to burn energy and sustain a constant temperature. Ectotherms’ metabolic rates increase as their body temperature increases.

Homeothermic endotherms employ various strategies to regulate temperature:

  • Shivering (muscle activity).
  • Behavioral changes (moving to warmer locations).
  • Insulation (fur, fat).
  • Utilizing uncoupling proteins.

Role of Uncoupling Proteins (UCPs)

Uncoupling proteins increase the permeability of the inner mitochondrial membrane, allowing protons to pass through without driving ATP synthase. This weakens the proton motive force, dissipating the energy as heat. Mammalian mitochondria often exhibit greater proton leakage (due to UCPs), generating more heat. Passive heat loss can also be limited by mechanisms like countercurrent exchange.