Biochemistry of the Metabolism


The Mitochondria

Story time

The story of the mitochondria stems back to the ages where predominantly, single-celled living forms ruled the earth, and a great battle between the prokaryotes and eukaryotes had been going on for millions of years.

  • Cells ingested each other through phagocytosis, digested, and used each other’s proteins and lipids as a source of energy (endosymbiotic theory)
  • The mitochondria used to live on its own, as a prokaryote. This tiny creature can provide a huge amount of energy, very efficiently
  • The general perception is that after the meeting of a eukaryote and this prokaryotic energy machine (the mitochondria), a proper and beneficial symbiosis was confirmed, whereby the eukaryotic cell got ATP, and the mitochondrial part could live in a more stable system (i.e. inside the cell)

To produce a massive amounts of ATP we need:

  1. A huge space
  2. Super-active enzymes

In the cell, we are capable of housing small and active compartments, and the morphology of mitochondria is perfect for that.


The mitochondria is composed of a double layer of a phospholipid membrane forming two compartments with inner and outer matrix, which serve for the separation of the biochemical processes.
Within the inner matrix, internal invaginations of the inner membrane form cristae, which increase the surface area; within the inner membrane you will find the terminal oxidation relating protein complexes (cluster proteins containing metals) and the ATP synthase (F0F1) (Figure 1).

Figure 1. The features of the mitochondria — Copyright ©

Functions and related metabolic processes

The primary role of the mitochondria is the production of ATP, the source of energy. But that’s not the only thing that happens within the mitochondria. DNA and protein synthesis, elongation and degradation of fatty acids, transportation of proteins and the fatty acid degradation based thermoregulation through the UCP1 system (Figure 2) can all occur within the mitochondria.

Figure 2. The features and functions of the mitochondria — Copyright ©

  • In the terminal oxidation/electron transport chain, electron transmission is accompanied by proton-gradiation between the two sides of the inner membrane. The formation of the proton gradient occurs through the complexes of the respiratory chain
  • The electrons reach the ubiquinone via complexes I and II by the oxidation of NADH, which produces significant energy. This energy, a part of it, is conserved so that respiration complexes (complex I-III-IV) oxidise protons from the mitochondrial matrix
  • The difference in the concentration of the protons leads to a pH difference, i.e., the matrix is more alkaline than the membrane. Thus, the proton motive force is formed, so the free energy reduction is converted into electrochemical energy
  • The protons spontaneously return to the matrix according to the electrochemical gradient, which results in a reduction in free energy and is transformed by ADP phosphorylation into chemical energy in the form of ATP
  • The 2 ATP synthesis of -220 kJ mol of energy from NADH oxidation is sufficient for 2 ATP from succinate. If ATP synthesis is inhibited, electron migration is blocked on the respiratory chain. ATP synthesis is performed by ATP synthase. If there is not enough ADP or inorganic phosphate, there is no ATP synthesis, proton flow into the matrix space
  • Proton gradients are formed because the inner membrane is impermeable to protons. The protons can return to the matrix through the proton channel, which is part of the ATP synthase, a multi-subunit enzyme. The enzyme consists of F0F1 subunits. F0 forms the proton channel, and F1 performs ATP synthesis (Figure 3)

Figure 3. Types of the adipose tissue and it’s mitochondrial features, focusing on the terminal oxidation — Copyright ©

Thus, the proton gradient on both sides of the internal membrane of the mitochondria and the ATP synthesis are related as follows:

  • The reorganization of NADH and FADH2 at catabolic pathways occurs through respiratory complexes in the inner membrane of the mitochondria (Complex I-II). The energy generated during the back oxidation of reduced coenzymes is used for the ATP synthesis from oxidative phosphorylation complexes from ADP and inorganic phosphate. This means that the ATP-synthesizing enzyme complex utilizes the energy released during NADH and FADH2 oxidation by the respiration complex
  • The internal membrane of the mitochondria can become permeable to protons by specific agents, such as 2-4-dinitrophenol, thus dissociating electron transport and phosphorylation because no proton-gradient can occur.
  • Thermogenin is a dissociation protein that works similarly to 2-4-dinitrophenol. In brown fat (a special type of adipose tissue rich in mitochondria, capable of generating heat), the role of non-ATP is due to disintegration, but also UCP1, which is an essential protein in heat regulation.

Clinical correlation

The mitochondrial DNA consists of 16569 base-pairs of circular DNA of a bacterial origin, forming 37 genes which encode for:

  • 13 proteins
  • rRNAs
  • tRNAs

Respiratory chain proteins encoded by the human mitochondrial genome: NADH dehydrogenase, succinate dehydrogenase, ubiquinone cytochrome C dehydrogenase, cytochrome oxidase, ATP synthetase.

There are points in the mitochondria where mutations can lead to diseases. For example, LHON mutation site (Leber’s optical neuropathy) and MERRF syndrome (Myoclonic epilepsy and ragged-red fibre disease). Mutations and injuries of the mitochondrial genome are more dangerous because the genome is close to the inner surface of the inner membrane, which is more vulnerable than nuclear DNA. Reactive oxygen radicals can be produced in large quantities by which there are no protective histone proteins; there is no DNA repair system.

Figure 4. LHON syndrome in a patient’s point of view — Copyright ©

Many of the mutations are generated by replication errors, which can not be corrected or repaired. During the aging process, with time, such genetic errors are become more common. Since the proteins of the respiratory chain (I, II, III, IV, V complexes) are encoded in the mitochondrial genome, and if mutated are injured, metabolic problems may occur. Some specific mutations may even cause crystals to appear within the mitochondria.

General features and diseases of the mitochondria

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