--- module: 003-01 language: en chapter: 3 title: "Genes, Proteins, Adaptation, Injury, and Cell Death" module_title: "Foundations" source_sha256: f9ffbfb705bb39cf840463c25ea0f9f5a2e1331e9cd731a5adf9b94c4213ddf7 --- # Genes, proteins, adaptation, injury, and cell death ## Orientation ### Disease begins when a cell cannot maintain itself ### Outcome depends on stress, intensity, duration, cell type ### Mild stress: adaptation ### Severe but brief stress: reversible injury ### Persistent or overwhelming injury: cell death ### Cellular events scale up to organ failure ## Information flow and protein function ### DNA stores information in nucleotide sequence ### Transcription produces RNA #### mRNA processed, then translated by ribosomes ### Gene to protein is useful but incomplete #### Alternative splicing yields different transcripts #### Protein cleaved, modified, folded, transported, destroyed #### Phenotype depends on regulation at many levels ### Expression responds to hormones, nutrients, oxygen ### Epigenetics: histone modification, DNA methylation #### Stable change without altering sequence ## Mutation and inheritance ### Substitution, insertion, deletion, copy number, rearrangement ### Synonymous change may preserve the amino acid ### Missense substitutes, nonsense adds a stop codon ### Regulatory variants change expression, not sequence ### Dominant: one altered allele influences phenotype #### Does not mean common, severe, or beneficial ### Recessive usually needs both alleles affected ### Mitochondrial DNA mainly via the oocyte #### Heteroplasmy gives variable severity ### Penetrance: proportion expressing the phenotype ### Expressivity: variation in degree or form ## Why an altered allele can be dominant ### Loss of function often behaves recessively ### Haploinsufficiency: remaining output inadequate ### Dominant negative: altered protein blocks the normal one #### Both enter a complex needing working subunits ### Gain of function: excess, misplaced, or new activity ### Same gene, different disorders by mechanism ### A pedigree does not identify the mechanism ## Cellular adaptation ### Hypertrophy: increased cell size #### Workload with limited capacity to divide #### Later fibrosis and impaired relaxation cause harm ### Hyperplasia: increased cell number #### Physiological in pregnancy, pathological with oestrogen #### Not cancer, but some forms raise risk ### Atrophy: reduced size and sometimes number #### Synthesis falls, degradation and autophagy rise #### Conserves resources but reduces reserve ### Metaplasia: reversible switch of cell program #### Smokers: squamous epithelium loses mucociliary function #### Persistent stress can lead to dysplasia ## Reversible cell injury ### Central problem: impaired ATP production #### Ischaemia cuts oxygen, substrate, waste removal #### Hypoxaemia lowers oxygen but may keep flow ### Pump failure: sodium and water in, potassium out #### Cells and organelles swell, calcium accumulates ### ER swells, ribosomes detach, synthesis falls ### Unfolded-protein response ### Restoring flow within the window rescues cells #### Reperfusion can add oxidant and calcium injury #### Timely reperfusion is still essential ## Irreversible injury and necrosis ### Mitochondrial failure and profound membrane damage ### Nuclear change: pyknosis through karyolysis ### Coagulative: outlines kept, ischaemic solid organs ### Liquefactive: brain infarction and abscesses ### Caseous: friable, classically tuberculosis ### Fat necrosis: lipase release or trauma ### Fibrinoid: immune-mediated vascular injury ### Biomarkers from released intracellular proteins #### Troponin shows injury, not its cause #### Aminotransferases show injury, not liver function ## Apoptosis and regulated death ### Removes cells with minimal leakage ### Intrinsic: mitochondrial proteins, cytochrome c ### Extrinsic: death receptors ### Both activate caspases ### Too little: cancer or autoimmunity ### Too much: neurodegeneration, immune depletion ### Necroptosis and pyroptosis add inflammation ### Autophagy recycles components via lysosomes #### Context, degree, timing matter more than labels ## Clinical integration ### Not diagnosed from one symptom or value ### Ask stress, vulnerable tissue, reversibility, reserve ### Treatment follows mechanism #### Restore perfusion, remove toxins, support organs ### Intervention itself can cause harm