Mitochondrial Damage

Slide 1 · Mitochondrial Damage

Mechanisms of cellular injury and death

From ATP failure to necrosis and intrinsic apoptosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

By the end of this lecture, explain:

Why oxygen deprivation, ROS, Ca²⁺, and toxins injure mitochondria

How ATP loss causes osmotic, metabolic, and synthetic disturbances

Why ROS formation and mitochondrial protein leakage change cell fate

How MPTP-associated necrosis differs from intrinsic apoptosis

Slide 3 · Mitochondria link injury to cell fate

Mitochondria both generate life-sustaining energy and participate in cell-death signaling.

Mitochondrion

ATP generation

Cell-death signaling

Failure of energy production disrupts ATP-dependent cellular functions.

Release of mitochondrial proteins can initiate intrinsic apoptosis.

Slide 4 · Cell injury has multiple interconnected targets

Mitochondria are one major target within a network of cellular injury.

Mitochondria

Membranes

Endoplasmic reticulum

Nucleus

Plasma membranes, ER protein handling, and DNA are also vulnerable.

A single insult can damage several components simultaneously.

Slide 5 · Normal mitochondria support oxidative phosphorylation

Mitochondrial electron transport couples oxygen reduction to ATP synthesis.

Schematic — mitochondrion

Electron transport

Membrane potential

ATP generation

ADP phosphorylation supplies most cellular ATP under aerobic conditions.

Energy-dependent membrane transport and biosynthesis rely on this ATP.

Slide 6 · Oxygen sustains mitochondrial ATP production

The electron transport system reduces oxygen during oxidative phosphorylation.

O₂ availability

Electron transport

ATP synthesis

Reduced oxygen supply disrupts mitochondrial energy generation.

Oxidative phosphorylation is especially important in nondividing cells.

Slide 7 · Glycolysis is a less efficient backup

Cells can generate ATP by glycolysis when oxygen is absent.

Glucose / glycogen

Glycolysis

Limited ATP

Glucose can come from extracellular fluid or glycogen stores.

Compared with oxidative phosphorylation, glycolysis produces less ATP.

Slide 8 · Two pathways contribute to cellular ATP

The relative importance of the pathways changes during oxygen deprivation.

Oxidative phosphorylation

Mitochondrial location

Uses oxygen

Major ATP source

Glycolysis

Cytosolic pathway

Can function without oxygen

Smaller ATP yield

Oxidative phosphorylation is oxygen dependent.

Glycolysis can continue without oxygen but cannot fully replace mitochondrial output.

Slide 9 · Mitochondria sense diverse injurious stimuli

Different insults converge on mitochondrial dysfunction.

O₂ deprivation

ROS / Ca²⁺

Toxic agents

Mitochondrial injury

Hypoxia and ischemia restrict oxygen supply.

Reactive oxygen species (ROS), increased Ca²⁺, and toxins also damage mitochondria.

Slide 10 · The nature and duration of injury matter

Mitochondrial injury is not automatically irreversible.

Brief / mild injury

Limited perturbation

Recovery possible

Reversibility depends on context

Severe / prolonged injury

Progressive dysfunction

Irreversible damage

Cell death may follow

Mild or brief injury may remain reversible.

Sustained severe injury can progress to irreversible dysfunction and death.

Slide 11 · Tissue vulnerability differs

The injured cell’s demands and adaptability influence consequences.

Cellular ATP demand

Adaptation capacity

Injury outcome

Cells with high aerobic ATP requirements have less tolerance for loss of energy supply.

The same insult can produce different responses in different tissues.

Slide 12 · Hypoxia directly threatens oxidative phosphorylation

Oxygen shortage impairs mitochondrial ATP synthesis.

Hypoxia

↓ Oxidative phosphorylation

↓ ATP

Cell dysfunction

Reduced ATP causes multiple downstream cellular abnormalities.

Hypoxia may also stimulate compensatory glycolysis.

Slide 13 · Ischemia also compromises nutrient delivery

A perfusion deficit restricts both oxygen and metabolic substrates.

↓ Blood supply

↓ Oxygen + nutrients

Energy deficit

Reduced oxygen limits oxidative phosphorylation.

Reduced nutrient supply restricts compensation through glycolysis.

Slide 14 · Raised cytosolic Ca²⁺ injures mitochondria

Increased cytosolic Ca²⁺ is a mitochondrial damaging stimulus.

↑ Cytosolic Ca²⁺

Mitochondrial dysfunction

Cell injury

Mitochondrial disturbance can amplify the consequences of cell injury.

Calcium-related injury also intersects with membrane damage.

Slide 15 · Reactive oxygen species target mitochondria

ROS are both causes and consequences of mitochondrial injury.

ROS exposure

Mitochondrial damage

Further ROS

ROS can injure cellular components including mitochondrial structures.

Incomplete oxidative phosphorylation can increase ROS production.

Slide 16 · Some toxins reduce ATP production

Chemical injury may compromise mitochondrial energy synthesis.

Toxin exposure

Impaired ATP production

Energy failure

Cyanide as an example of a toxin causing ATP depletion.

This can occur despite the presence of oxygen in the environment.

Slide 17 · Mitochondrial gene mutations are an additional route

Inherited mitochondrial gene defects can lead to disease.

Mitochondrial gene mutation

Organelle dysfunction

Inherited disease

This is a distinct mechanism from acute oxygen deprivation or poisoning.

Specific mitochondrial genetic syndromes are covered elsewhere.

Slide 18 · Distinct insults can converge on one organelle

Mitochondrial dysfunction integrates metabolic, oxidative, and toxic injury.

Hypoxia / toxin / ROS / Ca²⁺

Mitochondrial dysfunction

ATP / ROS / protein leakage

Different initiating events need not produce completely different downstream consequences.

ATP loss, ROS generation, and death signaling may coexist.

Slide 19 · Three major consequences organize the topic

Mitochondrial injury can produce energy failure, oxidative damage, and apoptotic signaling.

ATP depletion

ROS generation

Protein leakage

ATP depletion primarily contributes to functional failure and necrosis.

ROS increases injury; Release of proteins favors intrinsic apoptosis.

Slide 20 · ATP depletion begins with impaired production

Mitochondrial damage decreases oxidative phosphorylation.

Mitochondrial dysfunction

↓ Oxidative phosphorylation

↓ ATP

Energy supply falls before many later structural consequences appear.

ATP loss can also result from inadequate oxygen, nutrients, or certain toxins.

Slide 21 · Mitochondrial permeability transition worsens injury

Mitochondrial damage can lead to formation of a high-conductance channel.

Schematic — mitochondrion

Injury

MPTP opening

Potential loss

Robbins calls this the mitochondrial permeability transition pore (MPTP).

Pore opening links mitochondrial injury to loss of membrane potential.

Slide 22 · Membrane potential is essential for ATP synthesis

MPTP opening dissipates the mitochondrial membrane potential.

MPTP opening

↓ Membrane potential

OXPHOS failure

The electrochemical state necessary for oxidative phosphorylation is lost.

Failure of ATP production then becomes progressive.

Slide 23 · Energy failure can culminate in necrosis

Progressive ATP depletion is a central route from mitochondrial dysfunction to necrosis.

Mitochondrial damage

ATP exhaustion

Membrane injury

NECROSIS

The pathway disrupts ion transport, biosynthesis, and membrane maintenance.

Terminal injury includes irreversible damage of cellular membranes.

Slide 24 · ATP powers more than contraction or movement

Nearly every cellular synthetic and degradative pathway depends on ATP.

Transport

Protein synthesis

Lipogenesis

Phospholipid turnover

Major examples: Membrane transport, protein synthesis, and lipogenesis.

Phospholipid turnover also uses energy-dependent reactions.

Slide 25 · Severe ATP loss has widespread cellular effects

Major abnormalities when ATP falls to 5%–10% of normal.

ATP reserve falls

Pumps + synthesis fail

Cell injury worsens

This figure represents a textbook description, not a diagnostic clinical threshold.

Multiple essential processes become impaired at this degree of energy depletion.

Slide 26 · Na⁺/K⁺-ATPase requires continuous ATP

The plasma-membrane sodium pump maintains transmembrane ion gradients.

Na⁺/K⁺-ATPase

EXTRACELLULAR

CYTOSOL

Na⁺

K⁺

ATP available

Na⁺/K⁺-ATPase active

Schematic — movements across plasma membrane

Normal function opposes Na⁺ accumulation inside cells.

ATP depletion diminishes activity of this energy-dependent transporter.

Slide 27 · Pump failure changes cellular ion balance

ATP shortage lowers Na⁺/K⁺-ATPase activity.

Na⁺/K⁺ pump ↓

EXTRACELLULAR

CYTOSOL

Na⁺

K⁺

↓ ATP

↓ Sodium pump activity

Schematic — movements across plasma membrane

Na⁺ enters and accumulates intracellularly.

The intracellular K⁺ concentration falls.

Slide 28 · Water follows the intracellular solute gain

Net solute retention creates an osmotic drive for water entry.

Normal cell

Swollen cell

Schematic — osmotic water accumulation

The cell swells as intracellular water accumulates.

This is a key early manifestation of cell injury.

Slide 29 · Endoplasmic reticulum also dilates

ATP-depletion–related ionic and water imbalance affects organelles.

Normal ER

Dilated ER

Schematic — luminal dilation of endoplasmic reticulum

Robbins explicitly links sodium pump failure to ER dilation.

Cellular swelling and ER dilation are part of the reversible-injury spectrum.

Slide 30 · Cell swelling reflects altered homeostasis

The sequence explains a classic early morphology of cell injury.

Normal cell

Swollen cell

Schematic — osmotic water accumulation

ATP failure is the initiating biochemical defect.

Ion imbalance and osmosis translate the defect into visible cellular enlargement.

Slide 31 · Oxygen deprivation triggers metabolic adaptation

Declining oxidative phosphorylation shifts ATP production toward glycolysis.

Oxygen ↓

ATP ↓ / AMP ↑

Glycolysis ↑

Cellular AMP increases as ATP declines.

The response attempts to preserve energy supply rather than correct the initiating oxygen deficit.

Slide 32 · Energy shortage activates glycogen mobilization

Rising AMP to increased phosphorylase activity.

AMP ↑

Phosphorylase activity ↑

Glycogenolysis ↑

Glycogen breakdown supplies glucose for energy generation.

This is a compensatory response during oxygen shortage.

Slide 33 · Phosphofructokinase promotes glycolytic flux

Injury-related energy changes increase glycolytic activity.

ATP ↓ / AMP ↑

Phosphofructokinase ↑

Glycolysis ↑

Increased phosphofructokinase activity.

The pathway provides ATP even when oxygen is limited.

Slide 34 · Glycolytic compensation uses finite glycogen stores

Sustained anaerobic glycolysis consumes cellular glycogen.

Glycogen store

Increased breakdown

Store depletion

Stored glycogen can be depleted rapidly during ischemic stress.

The compensatory route cannot fully maintain normal ATP generation.

Slide 35 · Anaerobic metabolism causes lactate accumulation

Glycolysis in the absence of adequate oxygen produces lactic acid.

Anaerobic glycolysis

Lactic acid ↑

PH ↓

The biochemical consequence accompanies energy compensation.

This contributes to intracellular acidification.

Slide 36 · Inorganic phosphate also contributes to acidification

Hydrolysis of phosphate esters produces inorganic phosphate.

Phosphate ester hydrolysis

Inorganic phosphate ↑

Intracellular pH ↓

Lactate and phosphate accumulation with lower intracellular pH.

Metabolic and ionic disturbances occur in parallel.

Slide 37 · Low intracellular pH impairs enzyme function

Acidification reduces activity of many cytosolic enzymes.

Lactate / phosphate

Acidification

Enzyme activity ↓

Glycolysis is therefore a partial rescue with secondary biochemical costs.

This connects ATP loss to wider metabolic dysfunction.

Slide 38 · Energy deficit becomes self-limiting

Compensatory glycolysis does not avert injury indefinitely.

ATP reduction

Glycolytic compensation

Substrate depletion

Progressive injury

Glycogen stores fall while ATP production remains limited.

Persistent hypoxia shifts the balance toward severe metabolic and structural damage.

Slide 39 · Protein synthesis is an ATP-dependent process

Sustained ATP loss disrupts the protein synthetic apparatus.

ATP depletion

Rough ER disturbance

Translation ↓

Structural effects involve rough endoplasmic reticulum and polysomes.

The result is reduced cellular protein synthesis.

Slide 40 · Ribosomes detach from rough ER

Prolonged energy depletion alters ribosome–ER association.

Ribosomes attached

Ribosomes detached

Sustained ATP ↓

Ribosome detachment

Schematic — changes in translation apparatus

This represents a structural change in the machinery of protein production.

Loss of attached ribosomes impairs synthesis of proteins handled by rough ER.

Slide 41 · Polysomes dissociate as injury progresses

Ribosomal complexes are disrupted during severe energy failure.

Intact polysomes

Dissociated ribosomes

Energy depletion

Polysome dissociation

Schematic — changes in translation apparatus

Dissociation of polysomes.

Ribosome detachment and polysome disruption both reduce translation.

Slide 42 · Protein misfolding may add further injury

ATP depletion may increase the burden of misfolded proteins.

ATP failure

Protein handling disturbed

Misfolded proteins ↑

The ER is a major site of protein-handling stress.

This links mitochondrial energy failure to injury at another organelle.

Slide 43 · ATP also supports membrane lipid maintenance

Phospholipid turnover depends on energy-consuming reactions.

ATP ↓

Phospholipid synthesis ↓

Membrane vulnerability

Impaired ATP production can reduce phospholipid synthesis.

Compromised membrane maintenance increases susceptibility to injury.

Slide 44 · Calcium and phospholipases worsen membrane injury

Membrane damage can develop through several interacting processes.

Ca²⁺ ↑

Phospholipase activity ↑

Phospholipid breakdown

Ca²⁺-dependent phospholipases can increase phospholipid breakdown.

ATP depletion, ROS, and membrane injury are mechanistically interconnected.

Slide 45 · Severe injury damages multiple cellular membranes

Energy failure progresses beyond reversible swelling.

Mitochondrial membrane

Lysosomal membrane

Irreversible injury

Irreversible damage to mitochondrial and lysosomal membranes marks advanced injury.

Loss of cellular membrane integrity contributes to necrotic death.

Slide 46 · Lysosomal membrane injury amplifies necrotic damage

Lysosomal damage is part of the terminal injury sequence.

Severe cell injury

Lysosomal membrane damage

Enzymatic digestion

Compromised lysosomes release degradative enzymes within injured cells.

Lysosomal and mitochondrial injury often coexist in severe necrosis.

Slide 47 · Incomplete oxidative phosphorylation generates ROS

Disrupted mitochondrial electron transport can form reactive oxygen species.

Incomplete OXPHOS

ROS generation

Cellular injury

ROS are a major second consequence of mitochondrial dysfunction.

The resulting damage extends beyond the mitochondrion itself.

Slide 48 · ROS can damage membrane lipids

Lipid peroxidation compromises membrane integrity.

ROS ↑

Membrane lipid peroxidation

Permeability disturbance

This creates another route from mitochondrial dysfunction to membrane damage.

A damaged membrane loses normal barrier properties.

Slide 49 · ROS can modify cellular proteins

Oxidative injury affects proteins as well as membrane lipids.

ROS ↑

Protein oxidation / damage

Functional impairment

Proteins are one class of molecular targets identified by Robbins.

Protein damage contributes to loss of normal cellular function.

Slide 50 · ROS can injure nucleic acids

Nucleic acids are also vulnerable to reactive oxygen species.

ROS ↑

Nucleic-acid damage

Cellular stress

Oxidative damage is not confined to mitochondrial DNA.

The precise consequence depends on the site and extent of damage.

Slide 51 · Mitochondrial dysfunction and ROS can reinforce injury

ROS are both an upstream insult and a downstream product of disturbed respiration.

ROS injury

Mitochondrial dysfunction

Further ROS

The relationship helps explain the amplification of severe cellular injury.

This is a conceptual feedback loop, not a quantitative kinetic model.

Slide 52 · Mitochondria also regulate intrinsic apoptosis

Mitochondrial proteins participate in programmed cell-death signaling.

Cell stress

Mitochondrial protein release

Apoptosis

This pathway differs from energy depletion leading to necrosis.

Loss of survival signals and damage can activate pro-apoptotic machinery.

Slide 53 · BH3-only sensors respond to cellular stress

Intrinsic apoptosis uses regulated BCL2-family proteins.

Cellular stress

BH3-only sensors

BAX / BAK activation

Growth-factor withdrawal, DNA damage, and protein misfolding may activate BH3-only sensors.

These signals relieve restraint on the pro-apoptotic effectors BAX and BAK.

Slide 54 · BAX and BAK form mitochondrial membrane channels

Pro-apoptotic BAX and BAK enable release of mitochondrial proteins.

Schematic — mitochondrion

BAX / BAK activated

Membrane channel formation

Protein leakage

Channel formation as an initiating event of the intrinsic pathway.

Their action is specific to mitochondrial membranes.

Slide 55 · Cytochrome c leakage activates the apoptotic machinery

Release of mitochondrial cytochrome c triggers downstream assembly of the apoptosome.

Cytochrome c release

APAF-1 / apoptosome

Caspase-9

APAF-1 participates in apoptosome formation.

The cascade activates initiator caspase-9.

Slide 56 · Caspases execute intrinsic apoptosis

Initiator caspases activate downstream executioner caspases.

Caspase-9

Executioner caspases

Apoptotic cell

Executioner caspases dismantle cellular proteins and structures.

Programmed fragmentation differs from necrotic membrane rupture.

Slide 57 · BCL2-family balance regulates mitochondrial permeabilization

Pro- and anti-apoptotic signals determine whether the intrinsic pathway proceeds.

Anti-apoptotic restraint

BCL2 and BCL-XL

Help maintain mitochondrial integrity

Oppose inappropriate apoptosis

Pro-apoptotic signaling

BH3-only sensors respond to stress

BAX / BAK become activated

Mitochondrial proteins are released

Anti-apoptotic BCL2-family proteins help preserve mitochondrial integrity.

Stress-responsive sensors and BAX/BAK favor mitochondrial protein release.

Slide 58 · MPTP and BAX/BAK channels have different implications

Mitochondrial membrane changes do not constitute one interchangeable event.

MPTP-related injury

Loss of membrane potential

ATP synthesis failure

Progression toward necrosis

BAX/BAK-mediated injury

Mitochondrial protein leakage

Cytochrome c / caspases

Intrinsic apoptosis

MPTP opening disrupts membrane potential and ATP synthesis.

BAX/BAK channels permit protein release that activates intrinsic apoptosis.

Slide 59 · Necrosis and apoptosis have distinct proximal mechanisms

Both pathways can involve mitochondria, but they diverge mechanistically.

Necrotic route

Severe ATP depletion

Membrane damage

Loss of cell integrity

Apoptotic route

BAX/BAK channel formation

Caspase cascade

Ordered fragmentation

Necrosis: Progressive energy failure and irreversible membrane injury.

Apoptosis: Regulated protein release and caspase activation.

Slide 60 · Why one insult may produce different outcomes

Cell fate depends on injury severity and cellular context.

Stimulus

Intensity + duration

Cell state / energy reserve

Outcome

Mild injury may be reversible; Severe sustained injury often causes necrosis.

Some stresses engage the mitochondrial intrinsic apoptosis pathway.

Slide 61 · Clinical reasoning: Sudden oxygen deprivation

Illustrative scenario: Tissue becomes acutely hypoxic after loss of perfusion.

Ischemia

ATP ↓

Pump failure / glycolysis

Necrosis if sustained

Predict an early fall in oxidative phosphorylation and ATP.

Then predict increased glycolysis, cell swelling, and—if severe—necrosis.

Slide 62 · Clinical reasoning: Cyanide exposure

Illustrative scenario: A toxin blocks effective mitochondrial ATP generation.

Toxin

Oxidative phosphorylation impaired

ATP ↓

Cell injury

Identify the proximate metabolic problem: ATP failure.

Predict ion pump dysfunction and cellular swelling as consequences.

Slide 63 · Clinical reasoning: Protein-handling stress

Illustrative scenario: Cellular stress activates BH3-only proteins.

BH3-only signal

BAX / BAK

Cytochrome c

Apoptosis

Predict BAX/BAK-dependent mitochondrial protein release.

Then identify the apoptosome–caspase sequence as the death pathway.

Slide 64 · Integrated sequence: From mitochondrial dysfunction to necrosis

A multistep mechanism explains why ATP depletion is so damaging.

ATP ↓

Ionic / metabolic defects

Structural failure

Necrosis

Pump failure causes swelling; Metabolic adaptation produces lactate and acidity.

With persistence, protein synthesis and membranes are irreversibly injured.

Slide 65 · Integrated sequence: Mitochondrial route to apoptosis

Intrinsic apoptosis uses regulated mitochondrial membrane permeabilization.

BAX / BAK

Cytochrome c release

Caspase activation

Apoptosis

BAX/BAK channel formation releases cytochrome c.

Apoptosome and caspase activation produce apoptotic dismantling.

Slide 66 · The central distinction

Mitochondrial injury leads to different cell-death pathways depending on the dominant mechanism.

Energy failure → necrosis

Protein release → apoptosis

Loss of membrane potential and ATP favors necrotic injury.

Release of mitochondrial proteins through BAX/BAK channels favors apoptosis.

Slide 67 · Knowledge check: Match the mechanism

Use the initiating mitochondrial event to predict the downstream abnormality.

MPTP → membrane potential / ATP?

BAX/BAK → mitochondrial protein release?

MPTP opening: What happens to membrane potential and ATP?

BAX/BAK channel formation: Which apoptotic signaling event follows?

Slide 68 · Knowledge check: Explain cell swelling

Reconstruct the causal chain from a mitochondrial defect to a visible morphologic change.

Mitochondrial ATP ↓

Na⁺/K⁺ pump ↓

Water influx

Cell swelling

Discussion: Trace the mechanism step by step

Why does intracellular Na⁺ rise when ATP falls?

Why does the increase in intracellular solute enlarge the cell?

Slide 69 · Mechanisms to retain

A small set of linked mechanisms explains the central pathology.

ATP / pumps

MPTP / Δψm

ROS

BAX / BAK

Mitochondrial impairment → ATP depletion → pump and synthetic failure.

MPTP → loss of membrane potential; Incomplete OXPHOS → ROS.

BAX/BAK → protein release → intrinsic apoptosis.

Slide 70 · Source and scope

Primary teaching source

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

Chapter 2: Cell Injury, Cell Death, and Adaptations.

Core section: Mitochondrial Damage (pp. 46–47).

Adjacent context: Mechanisms of Cell Injury, Membrane Damage, and Intrinsic Apoptosis.

Illustrations are original editable teaching schematics; no clinical or histologic specimens are depicted.