Mitochondria

The mitochondrion (Greek mito, thread; chondrion, granule) is a highly compartmentalized organelle. The primary function of mitochondria is to house the enzymatic machinery for oxidative phosphorylation resulting in the production of adenosine triphosphate (ATP) and the release of energy from the metabolism of molecules.

A mitochondrion consists of an outer mitochondrial membrane and an inner mitochondrial membrane creating an intermembrane space between them. The inner mitochondrial membrane surrounds a large compartment called the matrix. The matrix is partitioned by infoldings of the inner mitochondrial membrane known as cristae. Cristae amplify the inner mitochondrial membrane on which ATP synthesis takes place.

Mitochondria contain DNA and RNA, including ribosomes to synthesize some of their own proteins in the matrix. Only 1% of mitochondrial proteins are encoded by mitochondrial DNA. Most of mitochondrial proteins are encoded by nuclear genes, synthesized in cytosol ribosomes and imported into mitochondria by targeting signals that are recognized by the translocase of the outer mitochondrial membrane complex (TOM) on the outer mitochondrial membrane. TOM is the most common entry route of imported mitochondrial proteins. Targeting polypeptide signals and chaperones (Hsp60 and Hsp70) enable proteins to reach the matrix.

The outer mitochondrial membrane is permeable. It contains porins, proteins that form aqueous channels permeable to water-soluble molecules with a reduced molecular mass (less than 5 kd), such as sugars, amino acids and ions. The inner mitochondrial membrane is impermeable to the passage of ions and small molecules.

The inner mitochondrial membrane is the site of electron-transport and proton (H⁺) pumping and contains the ATP synthase. Most of the proteins embedded in the inner mitochondrial membrane are components of the electron-transport chain, involved in oxidative phosphorylation.

The mechanism of ATP synthesis is called oxidative phosphorylation. It consists in the addition of a phosphate group to adenosine diphosphate (ADP) to form ATP and the utilization of O₂. It is also called chemiosmotic because it involves a chemical component (the synthesis of ATP) and an osmotic component (the electron-transport and H⁺ pumping process).

The mitochondrial matrix contains pyruvate (derived from carbohydrates) and fatty acids (derived from fat). These two small molecules are selectively transported across the inner mitochondrial membrane and then converted to acetyl coenzyme A (acetyl CoA) in the matrix.

The citric acid cycle converts acetyl CoA to CO₂(released from the cell as waste metabolic product) and high-energy electrons, carried by nicotinamide adenine dinucleotide (NADH) - and flavin adenine dinucleotide (FADH₂) - activated carrier molecules.

NADH and FADH₂ donate high-energy electrons to the electron-transport chain lodged in the inner mitochondrial membrane and become oxidized to NAD⁺ and FAD. The electrons travel rapidly along the transport chain to O₂ to form water (H₂O).

As the high-energy electrons travel along the electron-transport chain, energy is released by proton pumps as H⁺ across the inner mitochondrial membrane into the intermembrane space. The H⁺ gradient then drives the synthesis of ATP.

Note that:

1. The inner mitochondrial membrane converts the energy derived from the high-energy electrons of NADH into a different type of energy: the high-energy phosphate bond of ATP.

2. The electron-transport chain (or respiratory chain) contributes to the consumption of O₂ as a phosphate group is added to ADP to form ATP.

The components of the electron-transport chain are present in many copies embedded in the lipid bilayer of the inner mitochondrial membrane. They are grouped into three large respiratory enzyme complexes in the receiving order of electrons:

1. The NADH dehydrogenase complex.

2. The cytochrome b-c₁ complex.

3. The cytochrome oxidase complex.

Each complex is a system that pumps H⁺ across the inner mitochondrial membrane into the intermembrane space as electrons travel through the complex. If this mechanism did not exist, the energy released during electron transfer would produce heat.

Cyanide and azide are poisons that bind to cytochrome oxidase complexes to stop electron transport, thereby blocking ATP production.

Cytochrome c is a small protein that shuttles electrons between the cytochrome b-c₁ complex and the cytochrome oxidase complex.

When the cytochrome oxidase complex receives electrons from cytochrome c, it becomes oxidized and donates electrons to O₂ to form H₂O. Four electrons from cytochrome c and four H⁺ from the aqueous environment are added to each molecule of O₂ to form 2H₂O.

The H⁺ gradient across the inner mitochondrial membrane is used to steer ATP synthesis. ATP synthase is a large enzyme embedded in the inner mitochondrial membrane involved in ATP synthesis.

H⁺ flow back across the inner mitochondrial membrane down the electrochemical gradient through a hydrophilic route within ATP synthase to drive the reaction between ADP and Pi to produce ATP.

This reaction takes place in the enzymatic component of ATP synthase projecting into the mitochondrial matrix like a lollipop head. About 100 molecules of ATP are produced per second. About three H⁺ cross the ATP synthase to form each molecule of ATP. ADP molecules produced by ATP hydrolysis in the cytosol are drawn back into mitochondria for recharging to ATP. ATP molecules produced in the mitochondrial matrix are released into the cytosol for their use.

Mitochondria participate in apoptosis, steroidogenesis, and thermogenesis

Mitochondria participate in three significant functions:

1. Programmed cell death or apoptosis.

2. Steroidogenesis (production of steroid hormones).

3. Thermogenesis.

Concerning apoptosis, mitochondria contain procaspases-2, -3, and -9 (precursors of proteolytic enzymes), apoptosis initiation factor (AIF), and cytochrome c. The release of these proteins in the cytosol initiates apoptosis.

With regard to steroidogenesis, mitochondrial membranes contain enzymes involved in the synthesis of the steroids aldosterone, cortisol, and androgens.

Concerning thermogenesis, most of the energy from oxidation is dissipated as heat rather than converted to ATP. Uncoupling proteins (UCPs), members of the superfamily of mitochondrial anion-carrier proteins present in the mitochondrial inner membrane, mediate the regulated discharge of H⁺ (called proton leak), resulting in the release of heat. Proton leak across the mitochondrial inner membrane is mediated by UCP-1.

UCP-1 is present in the mitochondrial inner membrane of brown adipocytes. Its role is to mediate regulated thermogenesis in response to cold exposure.

Clinical significance: Mitochondrial maternal inheritance

Mitochondrial DNA (mtDNA) is transmitted by the mother (maternal inheritance). Both males and females can be affected by mitochondrial diseases, but males seem unable to transmit the disorder to the offspring. Maternal inheritance of mtDNA is regarded as an evolutionary advantageous event because of the potential damage of mtDNA by reactive oxygen species (ROS) involved in fertilization.

Motile sperm reaching the oviduct for fertilization eliminate their mtDNA before fertilization, leaving vacuolar mitochondria. Yet, residual mtDNA in the fertilizing sperm can be unevenly distributed in the zygote during early embryo development. Consequently, paternal mtDNA inheritance effects cannot be disregarded.

Myoclonic epilepsy with ragged red fibers (MERRF) is characterized by generalized muscle weakness, loss of coordination (ataxia), and multiple seizures. The major complications are respiratory and cardiac failure because the respiratory and cardiac muscles are affected. Muscle cells and neurons are the most affected because of their need for significant amounts of ATP to function.

Histologic preparations of muscle biopsies of individuals with MERRF display a peripheral red-stained material corresponding to aggregates of abnormal mitochondria, giving a ragged appearance to red muscle fibers. MERRF is caused by a point mutation in a mitochondrial DNA gene encoding tRNA for lysine. An abnormal tRNA causes a deficiency in the synthesis of proteins required for electron transport and ATP production.

Three maternally inherited mitochondrial diseases affect males more severely than females:

1. About 85% of individuals affected by Leber's hereditary optic neuropathy (LHON) are male. The disease is confined to the eye. Individuals suffer a sudden loss of vision in the second and third decades of life.

2. Pearson marrow-pancreas syndrome (anemia and mitochondrial myopathy observed in childhood).

3. Male infertility. Almost all the energy for sperm motility derives from mitochondria.