--- module: 003-02 language: en chapter: 3 title: "Genes, Proteins, Adaptation, Injury, and Cell Death" module_title: "Genome maintenance, organelle stress, and tissue consequences" source_sha256: 90e40fd4c0bb4e3394efca13af3868b941f2b9e529d0d1991d1b6aafd79bd03b --- # Genome maintenance, organelle stress, tissue consequences ## From variant to phenotype ### Disease only through a chain of consequences ### Does it change amount, location, timing, function? ### Phenotype depends on tissue, stage, exposure, reserve ### Loss of function reduces useful activity #### One normal allele enough: recessive #### Amount insufficient: haploinsufficiency, dominant ### Dominant negative interferes with normal product #### Both assemble into a larger structure ### Gain of function: excessive, constitutive, novel ### Mechanism suggests therapy better than the label ## Mosaicism and variant interpretation ### Mosaicism: variant arises after fertilisation #### Earlier events affect more tissues ### Somatic mosaicism: segmental disease or cancer ### Germline mosaicism: sibling recurrence #### Even with a negative parental blood test ### Mitochondrial threshold effects #### Symptoms when dysfunction exceeds tissue tolerance ### Interpretation combines frequency, segregation, function ### Uncertain significance is not a diagnosis #### Reclassification as evidence accumulates ### Consent and genetic counselling are essential ## Protein quality control ### Chaperones assist folding ### Ubiquitin tags misfolded proteins for proteasomes ### Autophagosomes deliver aggregates to lysosomes ### ER monitors secretory and membrane proteins #### Unfolded protein reduces translation #### Raises chaperone capacity and degradation #### Persistent stress triggers inflammation, apoptosis ### Proteostasis declines with ageing #### Damaged proteins seed further aggregation ### Aggregates may not be the only toxic species ## Mitochondria and oxidants ### Integrate energy, calcium, biosynthesis, death signals ### Divide, fuse, move, undergo quality control ### Fission and mitophagy remove damaged regions #### Failure: less ATP, more reactive oxygen species ### Reactive oxygen species also signal and defend ### Injury when production exceeds antioxidant capacity #### Respiratory chain, inflammatory cells, radiation ### Superoxide dismutase, catalase, glutathione limit damage ### Excess oxidants modify lipids, proteins, nucleic acids #### Open permeability pathways that commit to death ## Hypoxia and cancer metabolism ### Hypoxia-responsive transcription #### More glycolysis, angiogenic signalling #### Kidney-derived erythropoietin ### Cannot fully replace aerobic energy production ### Chronic activation aids remodelling, tumours ### Cancer cells reorganise metabolism for growth #### Aerobic glycolysis supplies biosynthetic intermediates ### Oxygen still matters in tumours ## Membrane injury and intracellular calcium ### Lipid peroxidation makes membranes leaky ### Impaired phospholipid repair and cytoskeleton damage ### Lysosomal disruption releases hydrolases ### Cytosolic calcium normally kept very low #### Injury allows entry and store release ### Calcium activates destructive enzymes #### Phospholipases, proteases, endonucleases ### Mitochondrial calcium worsens permeability, oxidants ### No single point of no return #### Cells cross the threshold at different times ## Patterns of regulated death ### Apoptosis: caspase cascade, membranes intact ### Intrinsic pathway: B-cell lymphoma two family balance ### DNA damage activates checkpoint proteins #### Pause, repair, or apoptosis if repair fails ### Extrinsic: death receptors recruit complexes ### Necroptosis: kinase-controlled membrane rupture ### Pyroptosis: inflammasome and pore formation ### Ferroptosis: iron-associated lipid peroxidation ### Tissue injury often mixes several pathways ### Necrotic release recruits inflammation ### Apoptotic cells signal quiet clearance #### Failed clearance: secondary membrane breakdown ## Tissue architecture, biomarkers, recovery ### Outcome depends on scaffold, microcirculation, location #### Small brainstem lesion can be devastating #### Patchy injury leaves viable bridges ### Biomarkers sample injury indirectly #### Level reflects release, distribution, clearance #### Serial change separates evolving from chronic ### Tissue markers locate injury, not mechanism ### Recovery: repair, proliferation, remodelling, scar ### Normal biomarker despite lost reserve ### Identify stress, judge reversibility, remove cause