Cell Biology: Epigenetics, Mitochondrial Inheritance, and the Endosymbiotic Theory

Administrative Announcements and Examinations

• Midterm Logistics:     - The midterm examination is scheduled for Wednesday of next week.     - Required Materials: Students must bring number two pencils, a valid student ID, and a UCD Scantron 2000 form. The department does not budget to provide these forms.     - Study Guide: A study guide has been posted for class review.     - Policy on Aids: No cheat sheets are allowed for the exam.     - Content Coverage: The exam covers Chapters 1 through 13. Chapter 13 is the first lecture of Module 3 but connects back to Modules 1 and 2.     - Weighting: Lecture material will be weighted more heavily than the textbook content.     - Format: The exam will be approximately 40 multiple-choice questions to be completed in a 50-minute period. The style mirrors previous two-unit quizzes and is tied to lecture learning goals.

• Upcoming Deadlines:     - Module 2 Quiz: Due tonight by 11:59 PM (covers textbook chapters 9 and 10).     - PSA Source Evaluations: Due on the first Friday of the month.     - PSA Final Outlines: Written outlines are due on the day indicated (refer to writing instructions).

• Review Sessions:     - Zoom Review: Monday, May 4, at 4:00 PM. This is a Q&A format led by TAs.

Epigenetics: The Regulatory Layer Above Genetics

• Definition of Epigenetics: Literally meaning "above genetics," it refers to regulatory mechanisms layered on top of DNA that determine gene expression without changing the DNA sequence itself.

• The Phenotype Equation: The core principle is $\text{Genotype} + ext{Environment} + ( ext{Genotype} imes ext{Environment}) = ext{Phenotype}$. Epigenetics represents the molecular interaction term between genes and the environment.

• DNA Compaction and Chromatin Architecture:     - Humans have approximately $2\,m$ of DNA packaged into a nucleus roughly 10\,microns wide.     - Chromatin: An elaborate coat of proteins, primarily histones, around which DNA is wrapped.     - Histones: Proteins that act as spools for DNA. The physical spacing of these histones dictates gene accessibility.     - Heterochromatin: Tightly packed histones that prevent DNA from being read or transcribed.     - Euchromatin: Widely separated histones that allow machinery like RNA polymerase to access and transcribe genes into mRNA.

• The Five Core Takeaways of Epigenetics:     1. DNA sequence changes are not the only way to alter gene expression (when, where, and how much).     2. Chemical Modifications (Post-Translational Modifications):         - DNA Methylation: Typically acts to shut down or silence gene expression.         - Histone Acetylation: Typically acts to turn on gene expression.     3. The same DNA can yield different outputs based on these regulatory layers.     4. Heritability: Epigenetic modifications can be inherited across cell divisions and sometimes across generations. If environmental stress changes chromatin in the germline, those changes can be passed to offspring.     5. Environmental Bridge: Epigenetics acts as the molecular bridge between the genome and environmental cues.

• The Library Metaphor:     - The Genome is like a giant library where every cell has the same books and chapters (identical DNA).     - The Cells are picky readers (e.g., neurons read neurotransmitter chapters like dopamine; skin cells read keratin chapters).     - Epigenetic Modifications are equivalent to Post-it notes on the pages. They tell the cell which chapters to focus on and which to skip. The environment can add or remove these "sticky notes."

Cellular Organization and Compartmentalization

• Cell Health and Protein Function: Organismal health depends on cells performing functions correctly. Defects at the molecular level lead to disease:     - Cancer: Dysregulated cell growth and metastasis (migration).     - Cystic Fibrosis: Broken ion channels in lung epithelial cells.     - Diabetes: Faulty insulin signaling.     - Neurodegenerative Disease (e.g., Parkinson’s): Neuronal protein aggregations.

• Prokaryotes vs. Eukaryotes:     - Prokaryotes (Bacteria and Archaea): Usually consist of a single compartment with DNA floating in the cytoplasm. Size is approximately 1 ext{ to } 2\,microns.     - Eukaryotes: Contain a nucleus and multiple specialized compartments (organelles). Size is approximately 10 ext{ to } 30\,microns.

• Size Scales in Biology:     - Cell: Tens of micrometers ($\mu m$).     - Nucleus: Average size of 10\,μm.     - Mitochondria: 1 ext{ to } 2\,μm (similar to bacteria).     - Ribosome: $20\,nm$.     - Protein: Single-digit nanometers ($nm$).     - Molecules: Approximately $0.2\,nm$.

• Benefits of Compartmentalization:     1. Varying Conditions: Different reactions require different pH or salt levels. For example, the Lysosome maintains a low, acidic pH to degrade faulty proteins or bacteria.     2. Concentration: Smaller volumes within membranes increase the concentration of reactants, making biochemical reactions faster.     3. Safety/Separation: Incompatible processes are kept apart. For instance, the degradative enzymes in a lysosome must stay enclosed so they do not digest the rest of the cell.

The Mitochondrion: Structure and Energy Synthesis

• Volume: Mitochondria can take up approximately $22\%$ of the cytoplasm volume in a eukaryotic cell, existing in hundreds to thousands of copies.

• The "Powerhouse" of the Cell: Its primary function is the production of ATP (Adenosine Triphosphate).

• ATP/ADP Cycle:     - ATP: The energy currency. It contains three phosphate groups. Cleaving the high-energy bonds between phosphates releases energy.     - ADP (Adenosine Diphosphate): The product after ATP is hydrolyzed to release energy. It must be recharged to become ATP again.     - Scale of Production: The human body produces and consumes between $50 ext{ to } 75\,kg$ of ATP every single day—roughly equivalent to one’s own body weight.

• Structure:     - Double Membrane: Consists of an outer and an inner membrane.     - Cristae: Folds of the inner membrane that increase surface area for ATP synthesis.     - Matrix: The innermost space within the inner membrane.

• Cellular Respiration:     - Equation: $\text{Sugars} + ext{Oxygen} ightarrow ext{ATP} + ext{Carbon Dioxide} + ext{Water}$.     - The True Purpose of Breathing: Oxygen is not inhaled simply for the lungs; it is delivered via hemoglobin to the mitochondria to drive ATP synthesis. Carbon dioxide exhaled is the byproduct of this mitochondrial process.

Mitochondrial Genetics and Maternal Inheritance

• Mitochondrial Genome (mtDNA):     - Unlike nuclear DNA, it is circular.     - Size: $16,569\,base\,pairs$.     - Gene Count: 37 total genes (13 encoding proteins, 22 making tRNAs, and 2 making rRNAs).

• Contrast with Nuclear Genome:     - Size: $3 imes 10^9\,base\,pairs$ ($3\,billion$).     - Gene Count: $20,000 ext{ to } 26,000\,genes$.     - Inheritance: Biparental (both parents).

• Strict Maternal Inheritance:     - Mitochondria are inherited only from the mother.     - Mechanism: The egg contains many mitochondria. Sperm have mitochondria at the base of the tail to power the flagella for swimming. During fertilization, only the sperm nucleus enters the egg; the sperm's mitochondria are typically excluded or destroyed. The resulting embryo keeps only the maternal mitochondria.

• Pedigree Analysis of Mitochondrial Disease:     - Patterns:         - Both sexes can be affected.         - Affected mothers pass the trait to all of their children.         - Affected fathers pass the trait to none of their children.     - Tissue Specificity: Diseases from mtDNA mutations primarily affect high-energy demand tissues.         - Symptoms: Brain (stroke, epilepsy, migraines), Eyes (optic neuropathy), Heart (cardiomyopathy), Liver (failure/jaundice), Pancreas (diabetes), Muscle (weakness, exercise intolerance), Peripheral nerves (neuropathy).         - Reasoning: Low-energy tissues (like skin or bone) are less affected because they require less ATP to function.

Evolutionary Origins: Endosymbiotic Theory

• The Theory: Proposed by Lynn Margulis (circa 1960s), stating that mitochondria were once free-living bacteria.

• Evidence for Bacterial Origin:     1. Size: Similar to bacteria (1 ext{ to } 2\,μm).     2. Structure: Double membranes, similar to certain bacteria.     3. Genome: Circular DNA, similar to bacterial chromosomes.

• Evolutionary Timeline: Approximately $1.5 ext{ to } 2\,billion$ years ago, an ancestral archaeal cell (eukaryotic ancestor) engulfed a bacterium. Instead of digesting it, a symbiotic relationship formed (mutualism). The bacterium provided ATP, and the host provided a stable environment. This partnership became permanent over time.

Clinical Cases and Mitochondrial Replacement Therapy (MRT)

• Specific Mitochondrial Diseases:     - Leber's Hereditary Optic Neuropathy (LHON): Sudden vision loss in young adults.     - MELAS: Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes.     - MERRF: Myoclonic Epilepsy with Ragged Red Fibers (affects muscle).     - Leigh Syndrome: Severe neurological disease in infants.

• Prevalence: Mitochondrial disease affects about $1 ext{ in } 4,300$ people, making it more common than Parkinson’s disease.

• Three-Person Baby Technology (MRT):     - Objective: Prevent maternal transmission of defective mitochondria by using a donor egg with healthy mitochondria while retaining the parents' nuclear DNA.     - Method 1: Pronuclear Transfer: The nucleus of the mother's egg (with defective mitochondria) is moved into a donor egg that had its nucleus removed.     - Method 2: Maternal Spindle Transfer: The mitotic spindle/nuclear material is removed from the mother’s egg during metaphase II of meiosis and placed into a donor egg.     - Result: The baby has nuclear DNA from two parents and mitochondrial DNA from a third donor. This was first legalized in the UK (2015) and has been done in Australia; the first child was born in 2016.

Questions & Discussion

• Question on Scantron Cost: A student asked if the "UCD scan cost $42,000" refers to a specific red form. The instructor clarified they did not know the cost or specific color, as this is their first undergraduate class, and simply advised getting the "UCD scan around 2000."

• Question on Radiation vs. Epigenetics: A student asked if radiation causing birth defects is epigenetics. The instructor corrected this, stating radiation affects the DNA sequence (genetics), whereas epigenetics refers to DNA accessibility for transcription.

• Question on Mental Illness: A student asked if mental illness is passed through epigenetics. The instructor noted that while stress effects could be passed epigenetically, most mental illnesses with a genetic component fall under traditional genetics, though the field is complex.

• Ethical Discussion Topics for Section:     - Is this considered genetic modification?     - Is the mitochondrial donor truly a parent?     - Who provides consent for future generations?     - Where is the line drawn for using this technology (e.g., only for severe disease or for milder conditions)?