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🔬 CELLULAR INJURY AND ADAPTATION

Complete 2nd MBBS Pathology Notes (Robbins-Based, MUHS Exam Ready)

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TOPIC 1 ⭐⭐ - MECHANISMS OF CELL INJURY & FREE RADICAL INDUCED CELL INJURY

Overview of Cell Injury

Major Causes of Cell Injury

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MECHANISMS OF CELL INJURY

1. ATP Depletion (Ischemic/Hypoxic Injury)

HYPOXIA / ISCHEMIA
        ↓
   ↓ Oxidative Phosphorylation
        ↓
      ↓ ATP
   ┌────────────────────────────────────┐
   │  ↑ Anaerobic glycolysis            │
   │  → ↑ Lactic acid                  │
   │  → ↓ pH (intracellular acidosis)  │
   └────────────────────────────────────┘
        ↓
   Na⁺/K⁺ ATPase pump fails
   Na⁺ & H₂O enter cell → Cell SWELLING
        ↓
   Ca²⁺ influx (↑ intracellular Ca²⁺)
        ↓
   Activates: Phospholipases → membrane damage
              Proteases → cytoskeletal damage
              Endonucleases → DNA damage
              ATPases → ↓↓ ATP

2. Mitochondrial Damage

• Loss of membrane potential (↓ΔΨm)
• Formation of mitochondrial permeability transition pore (MPTP)
• Release of cytochrome c → triggers apoptosis
• Accumulation of Ca²⁺ in mitochondria

3. Plasma Membrane Damage

• Direct trauma, toxins, complement activation
• Loss of selective permeability
• Influx of Ca²⁺, Na⁺, H₂O
• Efflux of K⁺, proteins, enzymes

4. Intracellular Ca²⁺ Accumulation

• Normal intracellular Ca²⁺: 0.1 μmol/L; extracellular: 1.3 mmol/L
• Increased Ca²⁺ activates:
  • Phospholipases → membrane damage
  • Proteases → cytoskeletal breakdown
  • Endonucleases → chromatin fragmentation
  • ATPases → ATP depletion

5. Defects in Membrane Permeability (Lysosomal Rupture)

• Release of lysosomal enzymes (acid hydrolases, proteases)
• "Autolysis" - digestion of own cell

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FREE RADICAL INDUCED CELL INJURY ⭐⭐

Definition

Types of Free Radicals

Generation of Free Radicals

Sources:
1. Normal metabolism (mitochondria) - 1-2% O₂ → O₂•⁻
2. Absorption of radiant energy (UV, X-ray)
3. Inflammatory cells (neutrophils, macrophages - "respiratory burst")
4. Reperfusion injury
5. Drugs/chemicals (CCl₄ → CCl₃• free radical)
6. Transition metals (Fe²⁺, Cu²⁺)

FENTON REACTION:
H₂O₂ + Fe²⁺ → OH• + OH⁻ + Fe³⁺
(most dangerous - hydroxyl radical)

Effects on Cells (Three Main Targets)

FREE RADICAL
    ├─── LIPIDS (Lipid Peroxidation)
    │    → Chain reaction of membrane phospholipids
    │    → Loss of membrane integrity
    │    → Cell death
    │
    ├─── PROTEINS
    │    → Oxidation of amino acids (esp. sulfhydryl groups)
    │    → Cross-linking → protein degradation
    │    → Enzyme inactivation
    │
    └─── DNA
         → Strand breaks, base modifications
         → Mutations → Cancer, Cell death

Antioxidant Defense Mechanisms

Reperfusion Injury

• Restoration of blood flow to ischemic tissue paradoxically increases damage
• Mechanism: Burst of free radicals on re-oxygenation
• Clinically important in: MI (thrombolysis), stroke, transplantation

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TOPIC 2 ⭐ - REVERSIBLE vs IRREVERSIBLE CELL INJURY

Reversible Cell Injury

Morphological Features

• Hydropic change / Cloudy swelling: Most common early change
• Fatty change: Accumulation of lipid vacuoles
• Cell and organelle swelling
• Plasma membrane blebbing (without rupture)
• ER dilation
• Mitochondria swelling (without MPTP opening)
• Nuclear clumping of chromatin (reversible)

Cellular Mechanism

• ↓ ATP → Na/K pump failure → Na⁺ & H₂O influx → cell swelling
• ↑ Anaerobic glycolysis → lactic acid → ↓ pH
• Clumping of nuclear chromatin

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Irreversible Cell Injury (Cell Death)

Hallmarks of Irreversible Injury

1. Severe mitochondrial damage with vacuolization
2. Large flocculent densities in mitochondria (Ca²⁺ deposits)
3. Plasma membrane rupture (complete)
4. Lysosomal rupture
5. Nuclear changes (karyolysis, karyorrhexis, pyknosis)

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COMPARISON TABLE ⭐ (MUHS FAVORITE)

Point of No Return

• Opening of mitochondrial permeability transition pore (MPTP)
• Severe, irreversible membrane damage

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TOPIC 3 ⭐ - FATTY CHANGE (STEATOSIS) & FATTY LIVER

Definition

Etiopathogenesis - Mechanisms of Fatty Change

NORMAL FAT METABOLISM IN LIVER:
Free Fatty Acids (FFA) from adipose tissue
        ↓
Enter hepatocytes
        ↓
Esterified to → Triglycerides
OR Oxidized → CO₂ + energy (ketone bodies)
OR Converted → Phospholipids
        ↓
Combined with APOPROTEIN → VLDL (lipoprotein)
        ↓
Secreted into blood

ABNORMAL (FATTY CHANGE):
Any step disrupted → Triglycerides accumulate in cell

Six Mechanisms (Robbins)

1. ↑ Entry of FFA into liver (e.g., starvation, DM - lipolysis ↑)
2. ↑ FFA synthesis within hepatocytes (alcohol)
3. ↓ FFA oxidation (hypoxia, CCl₄ poisoning)
4. ↑ Esterification to triglycerides (high carbohydrate diet)
5. ↓ Apoprotein synthesis (CCl₄, protein malnutrition)
6. ↓ VLDL secretion/export (CCl₄, alcohol, protein deficiency)

Causes of Fatty Liver

Types of Fatty Change

Morphology of Fatty Liver

• Large, yellow, greasy liver ("goose liver appearance")
• Weight: up to 3-6 kg (normal ~1.5 kg)
• Soft, pale yellow, edges rounded
• Leaves yellow stain on blade when cut

        Macrovesicular Fatty Change:
        ┌──────────────────────────┐
        │ ○○○ Large clear vacuoles │  ← Lipid droplets
        │ ○  ○  ○  ○  ○  ○       │    (dissolved in processing)
        │   [N] peripheral nucleus │  ← Nucleus pushed aside
        │ ○  ○  ○  ○  ○  ○       │
        └──────────────────────────┘
        SPECIAL STAIN: Oil Red O (frozen sections) - stains fat RED
        H&E: Clear vacuoles (lipid dissolved in processing)

• Centrilobular (zone 3) distribution in alcoholic fatty liver
• Periportal distribution in kwashiorkor
• Stain: Oil Red O (must use frozen sections)

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TOPIC 4 ⭐ - PIGMENTS - CLASSIFICATION & HEMOPROTEIN-DERIVED PIGMENTS

Classification of Pigments

A. EXOGENOUS PIGMENTS

B. ENDOGENOUS PIGMENTS

1. Hemosiderin
2. Bilirubin
3. Hematin
4. Porphyrin
5. Hematoidin

• Lipofuscin (wear and tear pigment)
• Melanin
• Ochronotic pigment

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HEMOPROTEIN-DERIVED PIGMENTS (DESCRIBE IN DETAIL) ⭐

1. HEMOSIDERIN

• Local hemosiderosis: Small amounts, localized
  • Old hemorrhage site (bruise turns yellow-brown)
  • Pulmonary hemosiderosis (brown induration of lung) - in LVF
• Systemic hemosiderosis: Widespread iron deposition
  • Causes: Hemolytic anemia, multiple transfusions, dietary iron overload
  • Organs: Liver, spleen, bone marrow, lymph nodes
  • No organ damage at this stage
• Hemochromatosis (Hemosiderosis + Organ Damage):
  • Primary (genetic): HFE gene mutation → ↑ iron absorption
  • Secondary: Multiple transfusions, thalassemia major
  • "Bronze diabetes" - liver cirrhosis + DM + skin pigmentation
  • Organ damage: Liver (cirrhosis → HCC), pancreas (DM), heart (DCM), skin (bronze), gonads (hypogonadism)

2. BILIRUBIN

Hemoglobin → Heme → Biliverdin → BILIRUBIN
                                      ↓ (unconjugated)
                                 Liver conjugation
                                      ↓ (conjugated)
                                 Bile → intestine
                                      ↓
                              Urobilinogen/Stercobilin

• Unconjugated: Pre-hepatic (hemolytic), hepatic
• Conjugated: Hepatic, post-hepatic (obstructive)

3. HEMATIN

• Ferric iron + porphyrin (no protein)
• Found in: Malaria parasites (hemozoin - malarial pigment)
• Brown-black granules in macrophages of spleen, liver, bone marrow
• Also: Formalin pigment (acid hematin) in tissues fixed in acid formalin

4. HEMATOIDIN

• Rhomboid/needle-shaped golden-yellow crystals
• Iron-FREE bilirubin derivative
• Found in old hemorrhages, away from vessels (anaerobic conditions)
• No staining by Prussian blue

5. PORPHYRINS

• Precursors of heme
• Accumulate in porphyrias (enzyme defects in heme synthesis)
• Causes: Photosensitivity, skin lesions, neurological symptoms
• Urine turns red/port-wine colored on exposure to light

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DISORDERS ASSOCIATED WITH HEMOPROTEIN-DERIVED PIGMENTS ⭐

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TOPIC 5 ⭐ - BROWN ATROPHY OF HEART

Definition

Lipofuscin (Wear-and-Tear Pigment)

• Also called: Lipochrome, Senility pigment
• Composition: Polymers of lipids + phospholipids + protein
• Origin: Peroxidation of polyunsaturated lipids of subcellular membranes (free radical damage)
• Stains: Golden-brown with H&E; PAS positive; Ziehl-Neelsen positive; autofluorescent
• Location in cell: Perinuclear (around nucleus)

Brown Atrophy of Heart

• Old age (senile atrophy)
• Severe cachexia (malnutrition, cancer)
• Chronic wasting diseases (TB, AIDS)

• Small, dark brown ("tobacco brown") heart
• Weight reduced (250-300 g vs normal 300-350 g)
• "Cor bovinum" opposite - this is SMALL
• Tortuous, prominent coronary arteries (because heart shrinks around them)

        Brown Atrophy Heart:
        ┌──────────────────────────────┐
        │ [N]←  ←perinuclear           │
        │  ●●●●● brown granules ●●●●●│  ← Lipofuscin granules
        │ Myofibril  │  Myofibril     │
        │    Small diameter fibers     │
        └──────────────────────────────┘

• Small myocardial fibers
• Golden-brown perinuclear granules (lipofuscin) in cardiomyocytes
• Normal nuclear structure

• Marker of aging and cachexia
• No significant functional impairment by itself
• Associated with underlying cause (cancer, TB, starvation)

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TOPIC 6 & 7 ⭐⭐ - NECROSIS - TYPES, CAUSES, MORPHOLOGY (WITH CASEOUS, COAGULATIVE, LIQUEFACTIVE IN DETAIL)

Definition of Necrosis

• Cell swelling → rupture
• Release of cellular contents → inflammation
• Always pathological

Nuclear Changes in Necrosis (Classic MUHS question)

KARYOLYSIS: Nucleus fades (DNase activity dissolves chromatin)
PYKNOSIS: Nucleus shrinks and becomes dark (dense, hyperchromatic)
KARYORRHEXIS: Fragmentation of nucleus into small pieces

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TYPES OF NECROSIS

1. COAGULATIVE NECROSIS ⭐⭐ (Most Common)

Ischemia/Hypoxia
      ↓
Protein denaturation (coagulation)
      ↓
Cell enzymes inactivated
      ↓
Cell outlines preserved for days-weeks
      ↓
Eventual removal by phagocytes

• Myocardial infarction (MI) - most classic
• Renal infarction
• Splenic infarction
• Liver (Zahn infarction)

• Gross: Pale, firm area (white/pale yellow infarct), wedge-shaped
• Micro:
  • Preserved cell outlines ("ghost cells" or "tombstone pattern")
  • Pyknosis, karyorrhexis, karyolysis of nuclei
  • Eosinophilic (pink) cytoplasm (coagulated protein)
  • Inflammatory infiltrate at periphery

COAGULATIVE NECROSIS (Microscopy):
┌─────────────────────────────────┐
│ ▓▓▓▓ ▓▓▓▓ ▓▓▓▓ ▓▓▓▓           │  ← Preserved cell outlines
│ □    □    □    □               │    (Ghost cells)
│ ▓▓▓▓ ▓▓▓▓ ▓▓▓▓ ▓▓▓▓           │
│ No nuclei / pyknotic nuclei     │
│ Eosinophilic cytoplasm          │
└─────────────────────────────────┘

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2. LIQUEFACTIVE NECROSIS ⭐⭐

Bacterial infection OR Brain ischemia
        ↓
Hydrolytic enzymes digest cells
        ↓
Liquid, creamy mass (pus)
        ↓
Cavity formation

• Brain has HIGH lipid content + lots of hydrolytic enzymes
• Poor structural proteins → no scaffold to maintain outlines

• Brain infarct (ischemic stroke) - forms cystic cavity
• Bacterial abscess (pyogenic) - pus = dead neutrophils + liquefied tissue
• Amoebic abscess (liver)
• Pancreatitis (enzymatic necrosis)

• Gross: Soft, liquid, creamy-white pus OR cystic cavitation
• Micro:
  • Loss of cell structure
  • Accumulation of dead neutrophils (in abscess)
  • Foamy macrophages
  • Granulation tissue at periphery

LIQUEFACTIVE NECROSIS (Brain):
┌─────────────────────────────┐
│    . . . . . . . . .        │  ← Liquid, no structure
│   . . . . . . . . . .       │
│    CYSTIC CAVITY            │
│   . . . . . . . . . .       │
│ [Macrophages at periphery]  │
└─────────────────────────────┘

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3. CASEOUS NECROSIS ⭐⭐

• Also: Fungal infections (Histoplasma, Blastomyces)
• Sarcoidosis (non-caseating granuloma - the absence distinguishes it)

M. tuberculosis
      ↓
Macrophages engulf bacilli
      ↓
T-cell mediated hypersensitivity (Type IV/DTH)
      ↓
Granuloma formation
      ↓
Central caseous necrosis
(Combination of coagulation + partial liquefaction)

• Gross: Soft, cheesy, friable, yellowish-white material
• Micro:
  • Amorphous, granular, eosinophilic debris
  • NO cell outlines (unlike coagulative)
  • NO nuclear staining
  • Surrounded by epithelioid cells + Langhans giant cells + lymphocytes = granuloma
  • Peripheral fibrosis (capsule)

CASEOUS NECROSIS - GRANULOMA:
        ┌─────────────────────────────────┐
        │ [Lymphocytes][Lymphocytes]      │  ← Outer zone
        │   [Epithelioid cells]           │  ← Middle zone
        │  [Langhans Giant Cell]          │  ← (Horseshoe nuclei)
        │        ///CASEUM///             │  ← Central caseous necrosis
        │      amorphous debris           │    (cheese-like)
        └─────────────────────────────────┘
Langhans Giant Cell: Nuclei arranged at PERIPHERY of cell in horseshoe/ring pattern

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4. FAT NECROSIS

• Enzymatic fat necrosis - Acute pancreatitis (pancreatic lipases digest peripancreatic fat)
• Traumatic fat necrosis - Trauma to breast tissue

• Gross: Chalky-white deposits (saponification) - "chalk patches"
• Micro: Ghost fat cells with calcified saponified areas; inflammatory infiltrate
• Saponification: FFA + Ca²⁺ → Calcium soaps (chalky white)

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5. FIBRINOID NECROSIS

• Malignant hypertension
• Polyarteritis nodosa
• SLE
• Rheumatic fever (Aschoff nodules)

• Pink, homogeneous, fibrin-like deposits in vessel walls
• "Amorphous insudation" of plasma proteins
• Stains pink with H&E (resembles fibrin)

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6. GANGRENOUS NECROSIS (See Topic 10 for comparison table)

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SUMMARY TABLE OF NECROSIS TYPES

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TOPIC 8 ⭐⭐ - APOPTOSIS

Definition

• Activation of endogenous suicide program
• Energy-dependent (requires ATP)
• No inflammation (cell contents not released)
• Controlled, orderly process

NECROSIS vs APOPTOSIS (Key Comparison Table) ⭐

Examples of Apoptosis

• Embryogenesis (organ sculpting - formation of fingers)
• Thymus: Deletion of self-reactive T-cells (negative selection)
• Post-lactation breast involution
• Endometrial shedding (menstruation)
• Normal cell turnover in intestinal crypts
• Deletion of cells after immune response

• DNA damage (radiation, drugs) → p53 activation
• Viral hepatitis (Councilman bodies = apoptotic hepatocytes)
• Graft-vs-Host disease
• Neurodegenerative diseases (Alzheimer's, Parkinson's)
• Ischemically injured cells (border zone of infarct)

Mechanisms of Apoptosis

PATHWAY 1: INTRINSIC (Mitochondrial) Pathway

DNA damage / Oxidative stress / Growth factor withdrawal
                    ↓
           ↑ Pro-apoptotic proteins:
           BAX, BAK (Bcl-2 family)
                    ↓
     (Normally inhibited by BCL-2, BCL-XL)
     When pro-apoptotic > anti-apoptotic:
                    ↓
    Mitochondrial outer membrane permeabilization
                    ↓
    Release of CYTOCHROME C into cytoplasm
                    ↓
    Cytochrome C + APAF-1 + Caspase-9 = APOPTOSOME
                    ↓
    Activation of Caspase-3 (EXECUTIONER)
                    ↓
         APOPTOSIS (see below)

PATHWAY 2: EXTRINSIC (Death Receptor) Pathway

FasL binds Fas (CD95) receptor
OR
TNF binds TNFR1
              ↓
    FADD (adapter protein) recruited
              ↓
    Activation of Caspase-8
              ↓
    Activation of Caspase-3 (EXECUTIONER)
              ↓
         APOPTOSIS

EXECUTIONER PHASE (Caspase-3 Activation)

Caspase-3 (Executioner Caspase)
         ↓
    Activates DNase → DNA fragmentation into nucleosome-sized fragments
    Cleaves cytoskeletal proteins → Cell shrinkage
    Activates transglutaminase → Cross-linking
         ↓
Formation of APOPTOTIC BODIES
(Membrane-bound fragments of cell contents)
         ↓
Phagocytosed by macrophages/neighboring cells
(NO INFLAMMATION)

Morphological Changes in Apoptosis

1. Cell shrinkage (opposite of necrosis swelling)
2. Chromatin condensation (pyknosis) - dense, crescent-shaped
3. Cytoplasmic blebs form on membrane surface
4. Fragmentation into apoptotic bodies
5. Phagocytosis of apoptotic bodies - NO inflammation

Histological Appearance

• Single, scattered shrunken cells
• Dense, dark (hyperchromatic) nuclei
• Deeply eosinophilic cytoplasm
• Councilman bodies (eosinophilic round bodies) in liver - viral hepatitis

p53 and Apoptosis

• p53 = "Guardian of the genome"
• DNA damage → ↑p53 → activates BAX → intrinsic apoptosis
• Loss of p53 → cancer cells evade apoptosis

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TOPIC 9 ⭐ - DYSTROPHIC vs METASTATIC CALCIFICATION

Pathological Calcification

COMPARISON TABLE ⭐ (MUHS Exam Favorite)

Mechanism of Dystrophic Calcification

Dead/dying cells
      ↓
Membrane damage → Ca²⁺ influx
      ↓
Mitochondrial Ca²⁺ overload
      ↓
Release of phosphatases
      ↓
Phosphate + Ca²⁺ → Ca₃(PO₄)₂ crystals
      ↓
Hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) deposited

Causes of Metastatic Calcification (Hypercalcemia)

• ↑ PTH: Primary hyperparathyroidism, parathyroid adenoma
• Destruction of bone: Multiple myeloma, bone metastases, Paget's disease
• Vitamin D disorders: Hypervitaminosis D, sarcoidosis (↑1,25-VitD)
• Milk-alkali syndrome

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TOPIC 10 ⭐ - DRY vs WET GANGRENE

Gangrene

COMPARISON TABLE ⭐

GAS GANGRENE (Special type of Wet Gangrene)

• Caused by: Clostridium perfringens
• Produces gas (crepitus felt on palpation)
• Rapidly fatal if untreated
• Treatment: Hyperbaric O₂ + antibiotics + surgery

Internal Gangrene

• Strangulated bowel
• Wet type - rapidly fatal peritonitis

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TOPIC 11 ⭐⭐ - CELLULAR ADAPTATIONS

Definition

Types: ATROPHY, HYPERTROPHY, HYPERPLASIA, METAPLASIA

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1. HYPERTROPHY ⭐⭐

• Occurs in non-dividing (permanent) cells (cardiac muscle, skeletal muscle, neurons)

Increased workload / Hormonal stimulation
             ↓
Mechanical stress / Growth factors (IGF-1, TGF-β)
             ↓
Signal transduction (PI3K/Akt pathway, MAPK)
             ↓
Transcription factors activated (GATA4, NFAT)
             ↓
↑ Synthesis of structural proteins
             ↓
↑ CELL SIZE (more organelles, myofibrils)

• Pressure overload (hypertension, aortic stenosis) → Concentric hypertrophy (wall thickens, cavity unchanged)
• Volume overload (MR, AR) → Eccentric hypertrophy (wall thickens + cavity dilates)
• Long-standing → Decompensation → Heart failure

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2. HYPERPLASIA ⭐⭐

• Occurs in dividing (labile or stable) cells

Growth factors (EGF, HGF, FGF) / Hormones (estrogen)
                ↓
Receptor activation → PI3K/Akt, RAS-MAPK
                ↓
G1 phase entry → CDK-cyclin activation
                ↓
G1 → S → G2 → M (Cell division)
                ↓
↑ NUMBER of cells

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3. ATROPHY ⭐⭐

Decreased workload / Denervation / Loss of blood supply
                ↓
Activation of ubiquitin-proteasome pathway
Activation of autophagy (lysosomes digest own organelles)
                ↓
↓ Cell size + ↓ Number of organelles
        ↓
ATROPHY (with lipofuscin accumulation)

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4. METAPLASIA ⭐⭐

Chronic irritation/inflammation/Vitamin A deficiency
                ↓
Reprogramming of stem cells (not differentiated cells)
                ↓
Stem cells differentiate into new cell type
                ↓
METAPLASIA

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SUMMARY DIAGRAM OF ADAPTATIONS

                    CELL ADAPTATION
                          │
        ┌─────────────────┼─────────────────┐
        │                 │                 │
     SIZE UP           SIZE DOWN        TYPE CHANGE
   HYPERTROPHY          ATROPHY          METAPLASIA
        │                                    │
     NUMBER UP                         NUMBER UP
   HYPERPLASIA                        (cell division)

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TOPIC 12 ⭐ - CELLULAR AGING

Definition

Mechanism of Cellular Aging (Robbins - Key Mechanisms)

1. TELOMERE SHORTENING (Replicative Senescence)

Normal somatic cells have FINITE divisions (Hayflick limit = 50-70)
            ↓
With each cell division, TELOMERES shorten
(Telomeres = repetitive TTAGGG sequences at chromosome ends)
            ↓
Critically short telomeres activate p53
            ↓
Cell cycle arrest (G1 block) or Apoptosis
            ↓
CELL SENESCENCE (old, non-dividing cells)

• Telomerase maintains telomeres in: Germ cells, stem cells, cancer cells
• Absence of telomerase in somatic cells → aging
• Werner syndrome (premature aging): Defective DNA helicase → rapid telomere shortening

2. DNA DAMAGE ACCUMULATION

• ROS, radiation, chemicals cause DNA damage
• With age, DNA repair mechanisms become less efficient
• Accumulation of mutations → aging phenotype
• Also activates p53 → senescence/apoptosis

3. DEFECTIVE PROTEIN HOMEOSTASIS (PROTEOSTASIS)

• Aged cells: ↓ ability to fold proteins correctly
• ↑ Misfolded/abnormal proteins → Proteasome overloaded
• Accumulation of misfolded proteins → Cell dysfunction
• Relevant to: Alzheimer's (tau, Aβ), Parkinson's (α-synuclein), Prions

4. CALORIC RESTRICTION & SIRTUINS

• Caloric restriction extends lifespan in animal models
• Mechanism: Activates Sirtuins (deacetylases) → ↑ DNA repair, ↑ antioxidant defense
• TOR (target of rapamycin) pathway inhibition → longevity

5. FREE RADICAL (ROS) DAMAGE

• Mitochondria produce ROS as byproduct of metabolism
• ROS damage: DNA, proteins, lipids
• Accumulation of lipofuscin (seen as Brown atrophy)
• Mitochondrial damage → ↓ ATP production → aging

6. MITOCHONDRIAL DYSFUNCTION

• Aged mitochondria: ↓ membrane potential, ↓ oxidative phosphorylation
• Accumulation of damaged mitochondria (↓ autophagy/mitophagy)
• ↑ ROS from damaged mitochondria

Morphological Features of Aged Cells

• Small cell size (atrophy)
• Lipofuscin accumulation (perinuclear, golden-brown)
• Nuclear irregularity
• Lipid vacuoles
• ↓ Rough ER (↓ protein synthesis)
• Irregular mitochondria

Summary Diagram of Aging Mechanisms

                    CELLULAR AGING
                          │
    ┌─────────────────────┼──────────────────────┐
    │                     │                      │
TELOMERE          DNA DAMAGE              PROTEIN DAMAGE
SHORTENING        ACCUMULATION            (proteostasis↓)
    │                     │                      │
  p53 ↑             ↑ Mutations            Misfolded proteins
    │                     │                      │
  Senescence         Cell death            Aggregates (Amyloid)
    │
    └── HAYFLICK LIMIT

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EXAM QUICK-REFERENCE: MOST IMPORTANT POINTS FOR MUHS

⭐⭐ HIGH-YIELD FACTS:

1. Fenton reaction: H₂O₂ + Fe²⁺ → OH• (most dangerous free radical)
2. Coagulative necrosis - ISCHEMIA all organs except brain; Ghost cells
3. Liquefactive necrosis - BRAIN infarct + abscess (pus)
4. Caseous necrosis - TUBERCULOSIS; cheese-like; granuloma with Langhans giant cells
5. Caspase-3 = Executioner caspase (both pathways converge here)
6. BCL-2 = Anti-apoptotic; overexpressed in follicular lymphoma (t(14;18))
7. Telomere shortening = Most important mechanism of cellular aging
8. Dystrophic calcification = Normal Ca²⁺; Metastatic = High Ca²⁺ (Hypercalcemia)
9. Dry gangrene = Arterial occlusion, no infection, clear demarcation
10. Wet gangrene = Venous obstruction + infection, NO demarcation, spreads fast
11. Metaplasia involves reprogramming of STEM cells, not differentiated cells
12. Lipofuscin = Wear-and-tear pigment; Brown atrophy of heart; perinuclear; PAS+
13. Prussian blue stains hemosiderin; Perls' reaction
14. Oil Red O stains fat; requires frozen sections

⭐ ONE-LINE ANSWERS:

• Most common pigment: Melanin
• Wear-and-tear pigment: Lipofuscin
• Most common cause of cell injury: Hypoxia/Ischemia
• Most dangerous free radical: Hydroxyl radical (OH•)
• Enzyme converting O₂•⁻ to H₂O₂: Superoxide dismutase (SOD)
• Caseous necrosis always suggests: Tuberculosis (until proven otherwise)
• Apoptosis without inflammation: due to membrane-bound apoptotic bodies phagocytosed
• Hayflick limit: 50-70 divisions
• Most common cause of fatty liver worldwide: Obesity (NAFLD)
• Most common type of adaptation: Hypertrophy

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References: Robbins & Cotran Pathologic Basis of Disease, 10th Edition (Kumar, Abbas, Aster) - Chapter 2: Cell Injury, Cell Death, and Adaptations.

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What's Covered (All 12 Topics - MUHS Ready)

Tips for the MUHS Exam:

• Draw the granuloma diagram for caseous necrosis - Langhans giant cell with horseshoe nuclei always scores marks
• Draw the apoptosis pathway - both intrinsic and extrinsic with caspase cascade
• Comparison tables (reversible vs irreversible, necrosis vs apoptosis, dystrophic vs metastatic, dry vs wet gangrene) are direct 5-mark questions
• Free radicals question - always include Fenton reaction and the three targets (lipids, proteins, DNA)
• The ⭐⭐ topics (1, 6/7, 8, 11) are the most likely long essay (10-mark) questions