The Citric Acid Cycle and Endosymbiosis

Mitochondria structure

Mitochondria have an outer membrane and a folded inner membrane (cristae). The fluid filled center inside the inner membrane is the matrix, which is where pyruvate oxidation and the Citric Acid cycle take place

Endosymbiosis theory

proposed by Lynn Margulis in 1967

Explains that mitochondria (and chloroplasts) evolved from ancient free-living bacteria that were engulfed by early host cells

Evidence for Endosymbiosis

Mitochondria are self-replicating and roughly the same size as bacteria

Mitochondria have two membranes (the inner one resembles bacterial membranes)

Mitochondria contain their own circular DNA and bacterial-like ribosomes, enzymes, and transport systems

Pyruvate oxidation

before entering the citric acid cycle, pyruvate enters the mitochondrial matrix and is converted into Acetyl-CoA by the pyruvate dehydrogenase complex

Inputs: 2 Pyruvate (per glucose)

Ouputs: 2 Acetyl CoA, 2 CO2 (breathed out as waste), and 2 NADH

Pyruvate Oxidation Regulation

Turned ON (accelerated) by: Low-energy signals like NAD+, CoA, and AMP

Turned OFF (inhibited) by: High energy/product signals like ATP, Acetyl CoA, and NADH. It is also directly switched off via phosphorylation by a dedicated kinase when ATP is high, and switched back on my a phosphatase when ATP drops

The Citric Acid cycle

Once Acetyl CoA is made, it enters an 8-step circular pathway in the mitochondrial matrix

Because one glucose splits into two pyruvate, the cycle turns twice per glucose

How the Citric Acid Cycle starts and ends

The 2-carbon Acetyl CoA joins a 4-carbon molecule (oxaloacetate) via the enzyme citrate synthase to form 6-carbon citrate. Over 8 steps, carbons are stripped off as CO2 and electrons are harvested until Oxaloacetate is regenerate to start the loop again

Total Net Yield per Glucose of the Citric Acid Cycle

4 CO2

6 NADH

2 FADH2

2 ATP

Oxidation state of metabolites

As molecules move through the cycle from citrate>oxaloacetate, they lose electrons and become progressively more oxidized (citrate is the most reduced, oxaloacetate is the most oxidized)

Rate limiting step

The isocitrate dehydrogenase reaction (which oxidizes isocitrate to alpha-ketoglutarate and produces NADH and CO2) is the main rate-limiting step of the cycle

Slowest step that dictates the speed of the entire process

Citric Acid Cycle Regulation

Just like glycolysis, the Citric Acid Cycle slows sown via feedback inhibition when energy is abundant (ATP and NADH inhibit key enzymes) and speeds up when ADP is high

Kinase

adds a phosphate to a molecule

Phosphatases

removes a phosphate group

Dehydrogenases

catalyze redox reactions (transferring hydrogen atoms/electrons)

Isomerases

rearrange a molecule into an isomer (same formula, different structure)

synthases

combine two molecules together