Metabolic Disorders Of Tca Cycle & Oxidative Phosphorylation

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Beriberi

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Basic Cause: Neurological & cardiovascular [metabolic] disorder caused by a deficiency in thiamine (vitamin B1).

Biochemical Cause: Thiamine helps make up Thiamine pyrophosphate (TPP), a coenzyme of the pyruvate dehydrogenase complex, which converts pyruvate into acetyl CoA.

Affects the following other metabolic processes...

Pyruvate dehydrogenase (bridge b/w glycolysis & TCA)

Alpha-ketoglutarate dehydrogenase (TCA)

Transketolase (pentose phosphate pathway)

Alpha-ketoacid dehydrogenases (catabolism of aliphatic AAs)

Effect: Characterized by pain in the limbs, weakness of the musculature, distorted skin sensation, possible enlarged heart & low cardiac output.

Treatment: Thiamine supplements & follow-up blood work.

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Mad Hatter Syndrome

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Basic Cause: Metabolic disorder caused by exposure to mercury & arsenite.

Biochemical Cause: Mercury & arsenite have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the E2 component of the pyruvate dehydrogenase complex, which is inhibited.

Effect: Similar symptoms to Beriberi... Limb pain, weakness of the musculature, distorted skin sensation, possible enlarged heart & low cardiac output.

Treatment: Administration of reducing agents such as 2,3 mercaptopropanol, which can bind the metal ions & form a product that can be excreted in the urine.

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Rotenone Insecticide Exposure

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Basic Cause: Inhibits Complex I (NADH dehydrogenase) of electron transport chain.

Biochemical Cause: Inhibits transfer of electrons from iron-sulfur centers in Complex I to Ubiquinone (CoQ) by blocking oxidation of Fe-S clusters of Complex I. Prevents use of NADH as substrate. Complex I is unable to pass off its electron to CoQ, creating a buildup of electrons in the mitochondrial matrix. Cellular oxygen is reduced to the radical, producing ROS which damage DNA & other mitochondrial components.

Effect: Apoptosis of affected cells. Human intoxication very rare. Symptoms of exposure include irritation of mucosa, can cause vomiting.

Treatment: Decontamination/cessation of exposure, supportive care to diminish symptoms.

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Amytal Exposure

(Truth Serum)

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Basic Cause: Inhibits Complex I (NADH dehydrogenase) of electron transport chain.

Biochemical Cause: Inhibits transfer of electrons from iron-sulfur centers in Complex I to Ubiquinone (CoQ) by blocking oxidation of Fe-S clusters of Complex I. Prevents use of NADH as substrate. Complex I is unable to pass off its electron to CoQ, creating a buildup of electrons in the mitochondrial matrix. Cellular oxygen is reduced to the radical, producing ROS which damage DNA & other mitochondrial components.

Effect: Used to treat insomnia, anxiety, sometimes epilepsy.

Treatment:

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2,4-Dinitrophenol Overdose

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Basic Cause: Exogenous uncoupler, creating heat instead of ATP

Biochemical Cause: Proton uncoupler that transports protons back into the mitochondria, dissipating the proton gradient & bypassing ATP synthase - ATP not generated. Stimulates oxidation of more fuel, because system attempts to restore the proton gradient.

Effect: "Literally cooking to death". Skin rash, jaundice, severe BO, cataracts.

Treatment: Supportive care, glucocorticoids therapy, & hemoperfusion [method in which blood is pumped through device outside of patient's body, in efforts to remove toxins].

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Coenzyme Q Deficiency

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Basic Cause: Rare, because biosynthesis & dietary intake provide sufficient CoQ for healthy individuals.

Biochemical Cause: Limits passing of electrons on to Complex III.

Effect: Muscle weakness, encephalopathy, seizures.

Treatment: Oral CoQ supplementation.

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Azide Poisoning

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Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferric state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: Supportive medical care.

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Cyanide Poisoning

(Also binds to Hb, preventing it from carrying oxygen. Therefore in these poisonings, both oxygen transport & ATP synthesis are impaired.)

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Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferric state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: Cyanide antidote, oxygenation, continuous cardiac monitoring.

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CO Poisoning

(Also binds to Hb, preventing it from carrying oxygen. Therefore in these poisonings, both oxygen transport & ATP synthesis are impaired.)

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Basic Cause: Inhibits Complex IV.

Biochemical Cause: Inhibit electron transfer/ATP synthesis by binding tightly with the iron (in ferrous state) coordinated in Cyt a3.

Effect: Arrests electron transport.

Treatment: O2 administration.

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Arsenic Poisoning

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Basic Cause: Arsenic interferes with metabolic processes in multiple ways, resulting in multi-system organ failure.

Biochemical Cause:

Arsenate ion competes with G3P in glycolysis to inhibit ATP production.

Arsenite ion inhibits the PDH complex (link b/w glycolysis & TCA cycle).

Arsenic inhibits succinate dehydrogenase at level of TCA cycle.

Arsenic competes with phosphate to uncouple oxidative phosphorylation.

Arsenic inhibits heme synthesis.

Effect: These metabolic interferences lead to death from multi-system organ failure probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage.

Treatment: Supplemental potassium decreases risk of serious heart rhythm problem. Chelation therapy.

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Leigh's Disease

(Subacute Necrotizing Encephalomyelopathy - SNEM)

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Basic Cause: Disorder of oxidative phosphorylation - enzyme deficiency somewhere b/w PDH/ATP synthase

Biochemical Cause: ETC enzymes typically affected, either nuclear or mitochondrial DNA.

Effect: Characterized by movement disorders. Lactic acidosis common [Low BP, high HR, vomiting, rapid breathing].

Neuropathological issues - brain stem & basal ganglia are affected. Individuals usually only live into mid-teens.

Treatment: No cure, treatments include variations of vitamin & supplement therapies.

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Pyruvate Dehydrogenase Complex Deficiency

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Basic Cause: Disorder of oxidative phosphorylation

Biochemical Cause: Common cause is mutations in the X-linked E1 alpha gene [pyruvate dehydrogenase!!] PDH complex normally converts pyruvate into acetyl CoA, serving as bridge b/w carbs. & TCA cycle.

*5 coenzymes required*

1. NAD+ (made from niacin, B3)

2. FAD (made from riboflavin, B2)

3. Thiamine pyrophosphate/TPP (made from B1)

4. CoA (made from pantothenic acid/B5)

5. Lipoamide (made from lipoic acid)

Effect:

Metabolic form - Lactic acidosis [Low BP, high HR, vomiting, rapid breathing]

Neurological form - aspects similar to Leigh's Disease (brain stem & basal ganglia affected)

Treatment: Seizure control, ketogenic diet [high fat, low protein, low carbs. - forces body to use ketones for energy instead of glucose], sodium bicarbonate to alkalize metabolic acidosis.

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Mitochondrial Disorders

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The primary cause of mitochondrial disorders is a problem with the ETC. These are the most common neurometabolic disorders in children. They affect ~1 in 5,000 to 1 in 10,000 kids, are are typically progressive & very difficult to diagnose & treat.
Mutations in Complex I are the most common, including impaired NADH utilization, or poor electron transfer to Q.
More recently, mitochondria have also been found to play a central role in apoptosis. One thought is that the accumulation of mutations in mitochondrial genes over the course of decades contributes to aging, degenerative disorders, & cancer.