Oxidative Phosphorylation and Mitochondrial Function

Mitochondria (important)

• Site of oxidative phosphorylation

• own DNA

Bottlenecking

The number of mitochondria that develop from the oocyte is limited compared to the number of cells that the body will eventually develop; having just a few mutant mtDNA mitochondria could develop disease.

High metabolic demand (tissue)

• Nervous tissue

• Muscle tissue

Effect of the mutant mitochondrial is highly prominent

Types of mutated/non-mutated mtDNA

• Homoplasmy - Cells contain mutated/non-mutated mtDNA. Non-mutated mtDNA is relatively uncommon.

• Heteroplasmy: cells harbour wild-type and mutated mtDNA. The majority of mitochondrial disorders.

MELAS syndrome (Characterized)

• Stroke-like lesions in the brain that occur beginning in late-childhood/early adulthood.

• Sudden onset of headache, vomiting, seizures, migraines (increasing cognitive impairment after each episode)

MELAS (full name)

mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

MERRF (Full name)

Myoclonic epilepsy with ragged-red fibers

MERRF (genetics)

• Single mutation (A to G transition at nucleotide 8344 in the mitochondrial tRNA Lys gene)

MERRF (Symptoms)

• Myoclonic epilepsy

• Myopathy (muscle weakness)

• Neurological dysfunction

How does mitochondrial disease cause damage to other organs

• Types of toxic byproducts that the mitochondria produce: reactive oxygen species (superoxides, hydrogen peroxide)

• Attributed to the development of a number of diseases: Parkinsons, alzheimers, type II diabetes.

Inner Membrane (What occurs)

• Electron transport

• Oxidative phosphorylation

• Transhydrogenase

• Transport systems

• Fatty acid transport

Matrix (What occurs)

• Pyruvate dehydrogenase complex

• Citric acid cycle

• Glutamate dehydrogenase

• fatty acid oxidation

• Urea cycle

• Replication

• Transcription

• Translation

Outer Membrane (What occurs)

• Fatty acid elongation

• Fatty acid desaturation

• Phospholipid synthesis

• Monoamine oxidase

Multiple proteins work in tandem to

• Shut electrons from higher energy compounds (NADH, FADH2) using reducible intermediaries to the final lowest energy compound.end electron acceptor: oxygen.

• To use this energy from the shunting of these electrons to pump hydrogen atoms (protons) across the inner membrane space.

Main reducible proteins and coenzyme

• Flavoproteins

• Iron-Sulphur Proteins

• Coenzyme Q

• Cytochromes

Flavoproteins (Reducible proteins/coenzyme)

Proteins that contain the coenzyme, either flavin mononucleotide or flavin adenine dinucleotide (FAD)

Iron-Sulphur Proteins (Reducible proteins/coenzyme)

Proteins that use an iron-sulphur core that can be reduce for short periods of time

Coenzyme Q (Reducible proteins/coenzyme)

A hydrophobic membrane-residing protein, transferring electrons to complex III.

Cytochromes (Reducible proteins/coenzyme)

Used in many of the complex, but specifically cytochrome C, to shuttle electrons between complex III and complex IV

Complex 1: NADH-Coenzyme Q Reductase

First, NADH molecules attach to the proteins in the matrix to become ‘reoxidized’ back into NAD+.

Electrons get passed from NADH to flavin molecules, to iron sulphur compounds, to co-enzyme Q, which all help pump hydrogen across the membrane.

Complex 2: Succinate-Coenzyme Q Reductase

• Accepts electrons from the first complex and the citric acid cycle.

• Complex II is actually succinate dehydrogenase (the FADH that is reduced during that step in the cycle is within the protein itself).

• Transfers electrons down the chain to iron-sulphur groups, eventually to coenzyme Q, which is then transferred to complex III.

Complex 3 (Coenzyme Q: cytochrome c oxidoreductase)

• Accepts electrons from complexes I and II in the form of reduced coenzyme Q

• Forces out H+ ions through the energy gained by the transference if electrons.

Complex 4 (Cytochrome c Oxidase)

• Our final complex in the line, which helps create the proton gradient

• Uses copper, then an iron atom, to accept the electrons coming in from complex III and transfer them to oxygen.

Complex 5 (ATP synthase)

• Protein: ATP synthase

• Two main parts

• Whole protein complex together is known as the F0F1 complex

Complex 5 (two main parts)

• Rotor: Located within and through the membrane, which accepts protons flowing back through

• Stator: F1 knob, which physically attaches the ATP molecules from ADP and Pi and stabilizes the proteins.