TCA Cycle: Citric Acid Cycle (Krebs Cycle)

TCA Cycle

Location: mitochondrial matrix. Main purpose: Collect high-energy electrons, pass them to NADH/FADH₂, send them to ETC.

What TCA Produces

Input: 1 Acetyl-CoA (2 carbons)

Outputs:

• 3 NADH (electron carriers, loaded)

• 1 FADH₂ (electron carrier, loaded)

• 1 ATP (small amount)

• 2 CO₂ (carbons removed)

Per Glucose

Since 1 glucose → 2 pyruvate → 2 acetyl-CoA:

Per glucose:

• 6 NADH (3 × 2 turns)

• 2 FADH₂ (1 × 2 turns)

• 2 ATP (1 × 2 turns)

• 4 CO₂ (2 × 2 turns)

Where Acetyl-CoA Comes From

Main Source: Pyruvate from Glycolysis

Pyruvate (3 carbons) → Bridge step → Acetyl-CoA (2 carbons) + CO₂

Enzyme complex: Pyruvate dehydrogenase

What happens:

• Pyruvate is oxidized (loses electrons)

• CO₂ is released

• Acetyl group attaches to CoA

• NADH is produced

This bridge step is already energy extraction.

Why CO₂ is Released

Carbon Flow

Glucose: C₆H₁₂O₆

↓

Pyruvate: C₃H₆O₃ (twice)

↓

Acetyl-CoA: C₂H₄O (enters TCA)

In TCA:

• Carbons are progressively removed

• Released as CO₂

• Electrons are removed

• Given to NAD+/FAD

Result: All carbons eventually become CO₂.

Why Carbon Removal = Energy Release

When carbons are oxidized:

• Electrons are removed

• Electrons carry energy

• NAD+ accepts electrons

• NADH is formed

• NADH carries energy to ETC

CO₂ release is the SIGN that oxidation is happening.

Oxidation = energy extraction.

Why TCA is the Center of Metabolism

TCA is at the crossroads:

INPUTS:

• Carbs (via pyruvate → acetyl-CoA)

• Fats (via β-oxidation → acetyl-CoA)

• Proteins (via amino acids → acetyl-CoA or intermediates)

OUTPUTS:

• Electron carriers (NADH, FADH₂) to ETC

• Building blocks for biosynthesis (amino acids, nucleotides)

• Energy (ATP, via ETC)

Every fuel converges. Every energy need is met.

Oxygen and TCA: The Indirect Connection

TCA produces NADH.

NADH must be converted back to NAD+.

Where does that happen? At the ETC.

The ETC requires oxygen.

So:

No oxygen → ETC stops → NAD+ not regenerated → NADH accumulates → NAD+ runs out → TCA stops

Oxygen is required INDIRECTLY through NAD+ regeneration.

What If TCA Stops?

Oxygen Limited (Hypoxia)

Scenario: Limited oxygen (not zero)

What happens:

1. ETC slows (limited electron acceptor O₂)

2. NAD+ regeneration slows

3. NADH accumulates

4. TCA slows

5. Less ATP from ETC

6. Glycolysis may increase to compensate

7. Lactate production increases

Result: Cell survives but inefficiently.

Mitochondrial Dysfunction

Scenario: Mitochondrial disease (ETC broken)

What happens:

1. ETC cannot function

2. NAD+ cannot be regenerated

3. NADH accumulates

4. TCA slows/stops

5. ATP production fails

6. Increased reliance on glycolysis

7. Lactate accumulates

Result: Symptoms in high-ATP tissues (muscle, brain, heart)

Symptoms: Fatigue, weakness, myopathy

TCA and Fasting: The Oxaloacetate Problem

The Problem During Fasting

During fasting:

• Blood glucose drops

• Body must make new glucose

• Where? In liver via gluconeogenesis

Gluconeo genesis uses oxaloacetate (OAA).

OAA is a TCA intermediate.

So during fasting:

Oxaloacetate is diverted from TCA → used for glucose-making

TCA loses OAA → cannot accept acetyl-CoA efficiently.

What Happens to Acetyl-CoA?

With less OAA:

• Acetyl-CoA enters TCA but has nowhere to go

• Cannot combine with OAA to form citrate

• Acetyl-CoA accumulates in liver mitochondria

Prolonged fasting:

• Acetyl-CoA builds up even more

• Liver cannot use it all

• Alternative pathway activated: Ketone formation

Ketone Formation

Excess acetyl-CoA → Ketone bodies

Ketone bodies:

• Acetoacetate

• β-hydroxybutyrate

• Acetone (exhaled in breath)

Ketones are released into blood.

Brain and muscle use ketones as fuel.

This is ketogenesis. We'll see this more later.