Understanding Metabolism and Mitochondrial Function

  • ### Reminder of Upcoming Exam

    • Exam 3: Focuses solely on cytoskeleton material covering the last five lectures.

    • Content for Exam 3: Today's material is not included.

    • After Exam 3, the next writing assignment will be introduced.

  • ## Introduction to Today's Material

    • The focus today begins the coverage for Exam 4.

    • Topics to be discussed:

    • Organelles (specific focus on mitochondria)

    • Signal transduction

    • Extracellular matrix

  • ## Key Concepts Covered

    • ### Metabolism Overview

    • Metabolism: Defined as a network of integrated and regulated metabolic pathways contributing to cellular activities. These pathways are interconnected, allowing the cell to respond to changing conditions by adjusting the activity of specific enzymes. (Quote: "Life at the cellular level can be defined as a network of integrated and carefully regulated metabolic pathways, each contributing to the sum of activities that the cell actually does.")

    • ### Types of Metabolic Pathways

    • Anabolic Pathways: Responsible for producing cellular components.

      • Example: Assembling Legos to create a structure, such as synthesizing proteins from amino acids or complex carbohydrates from simpler sugars.

      • Processes increase molecular order and decrease entropy, meaning they create more complex, ordered structures from simpler, less ordered ones.

      • Endergonic Reactions: Require energy input (\Delta G > 0) to synthesize components (e.g., building polymers like microtubules, DNA replication).

    • Catabolic Pathways: Break down cellular components.

      • Example: Disassembling a Lego structure, leading to increased entropy (disorder) as complex molecules are broken into simpler ones.

      • Exergonic Reactions: Energy liberation occurs (\Delta G < 0) when bonds are broken, releasing stored energy (e.g., cellular respiration, breaking down glucose).

    • ### Importance of ATP

    • ATP (Adenosine Triphosphate): Main energy currency in cells.

    • Structure of ATP:

      • Composed of adenosine (adenine base + ribose sugar) and three phosphate groups.

      • The phosphodiester bond (linking ribose to the first phosphate) has low energy.

      • The two phosphoanhydride bonds (P-O-P bonds between phosphate groups) hold most energy, often referred to as "high-energy bonds".

    • Hydrolysis Reaction: Breaking ATP into ADP (Adenosine Diphosphate) and inorganic phosphate (Pi) or AMP (Adenosine Monophosphate) and pyrophosphate (PPi) releases about -7.3 kilocalories per mole of energy. ATP + H2O \rightarrow ADP + Pi + \text{Energy}. Hydrolysis involves water and is an exergonic reaction.

    • Energy Characteristics of ATP:

      • The substantial release of energy upon hydrolysis is due to:

      • Charge repulsion: The negative charges on the phosphate groups repel each other, becoming more stable when separated.

      • Resonance stabilization: The products (ADP and P_i) have greater resonance stabilization compared to ATP.

      • Increased entropy: The separation of one molecule into two increases disorder.

      • Enzymatic processes are not strictly required for hydrolysis in vitro; however, ATPases catalyze these reactions efficiently in cells.

    • ### Glycolysis Overview

    • Glycolysis: A sequence of ten reactions converting glucose (a 6-carbon sugar) into two molecules of pyruvate (a 3-carbon compound), producing a net gain of ATP and NADH. This process occurs in the cytoplasm and can proceed under both aerobic and anaerobic conditions. Not covered in depth but split into three phases:

      • Cleavage Phase: Converts one molecule of glucose into two molecules of glyceraldehyde-3-phosphate, requiring an initial investment of 2 ATP molecules.

      • Oxidative Phase: Producing NADH (an electron carrier) and ATP from glyceraldehyde-3-phosphate through substrate-level phosphorylation.

      • Final Phase: Rearrangement reactions resulting in two molecules of pyruvate and additional ATP molecules (net gain of 2 ATP per glucose).

    • Historically significant, discovered by Gustav Emden, Otto Meyerhof, and Otto Warburg.

    • ### Pyruvate Processing

    • Depending on oxygen availability, pyruvate can lead to:

      • Aerobic Conditions: Converted to acetyl CoA which then enters the citric acid cycle within the mitochondria for cellular respiration (mass ATP production).

      • Anaerobic Conditions:

      • In animals: converted into lactate (lactic acid fermentation) to regenerate NAD+ for glycolysis.

      • In yeast/plants: converted into ethanol and carbon dioxide (alcoholic fermentation) to regenerate NAD+.

    • ### Cellular Respiration and Chemiosmotic Coupling

    • Definition: Using oxygen as a terminal electron acceptor to produce ATP from glucose through a series of biochemical processes in the mitochondria.

    • Theoretical yield of ATP from cellular respiration: around 36 ATP, though actual yield varies (typically closer to 30-32 ATP) due to energy costs of transporting molecules and inefficiencies.

    • Chemiosmotic Coupling: Involves the establishment of an electrochemical proton gradient (H+ gradient) across the inner mitochondrial membrane, primarily by the electron transport chain. This potential energy stored in the gradient is then used to synthesize ATP via the integral membrane protein complex, ATP synthase.

  • ## Mitochondria Structure and Function

    • ### Structural Overview

    • Mitochondria: Often referred to as the powerhouse of the cell but have multiple functions beyond ATP production, serving as crucial signaling hubs.

    • Composed of an outer membrane, an inner membrane (folded into cristae), the intermembrane space (between the two membranes), and the matrix (innermost compartment).

    • Dynamic structures; their shape, size, and number depend on cellular energy needs, metabolic state, and stress levels, constantly undergoing fission and fusion.

    • ### Fission and Fusion Processes

    • #### Mitochondrial Fission

      • Necessary for removing damaged portions, segregating damaged mitochondria for degradation (mitophagy), and redistributing mitochondria within the cell to areas of high energy demand.

      • Main protein involved: Dynamin-related protein 1 (DRP1), a GTPase that assembles around the mitochondrion and constricts, assisting in pinching mitochondria apart.

      • Mitochondrial movement is affected by motor proteins (kinesin and dynein) that transport mitochondria along microtubules within cells.

    • #### Mitochondrial Fusion

      • Process that combines two mitochondria, essential for maintaining a healthy mitochondrial network, exchanging genetic material (mitochondrial DNA), and sharing metabolites or proteins to ensure functionality and distribution of healthy mitochondria.

      • Involves proteins Mitofusin 1 (Mfn1) and Mitofusin 2 (Mfn2) for outer membrane fusion and OPA1 (Optic Atrophy 1) for inner membrane fusion.

    • ### Membrane Dynamics

    • Outer Mitochondrial Membrane: Contains large pore-forming channels called voltage-dependent anion channels (VDACs), allowing the passage of small molecules, ions (like calcium), and metabolites between the cytosol and the intermembrane space—critical in neurotransmitter signaling, apoptosis, and metabolic exchange.

    • Inner Mitochondrial Membrane: Highly folded into cristae, significantly increasing its surface area. This membrane is the primary site of ATP synthesis, housing the electron transport chain complexes and ATP synthase responsible for generating electrochemical gradients necessary for ATP production. It is largely impermeable to ions.

    • Matrix Contents: A gel-like substance with a high protein content, housing enzymes for the citric acid cycle (Krebs cycle), mitochondrial DNA (circular, inherited maternally, encodes specific mitochondrial proteins), and ribosomes specific to mitochondrial protein synthesis.

    • ### Energy Production Insights

    • Mitochondria serve as primary energy production sites with distinct roles in metabolism, calcium signaling, and maintaining cellular homeostasis.

    • Process of Oxidative Phosphorylation: Involves the generation of ATP utilizing oxygen, occurring through two main stages: the electron transport chain (ETC) and chemiosmosis. The ETC uses a series of protein complexes to transfer electrons from NADH and FADH2, creating a proton gradient across the inner membrane for maximizing energy extraction from food substrates.

  • ## Conclusion

    • Emphasized the complexities of mitochondrial dynamics in energy production, their structural features, and their essential roles in cellular metabolism, leading into discussions for next week regarding oxidative phosphorylation and electron transport chains.

    • Students should prepare