OXPHOS system

Structure

The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome.

The great complexity of the OXPHOS system, which consists of about 85 proteins, some encoded by the mitochondrial genome and others by the nuclear genome, explains the wide variety of clinical phenotypes that are associated with genetic defects in oxidative phosphorylation.

The OXPHOS system is embedded in the lipid bilayer of the mitochondrial inner membrane and is composed of five multiprotein enzyme complexes (I-V) and two electron carriers - coenzyme Q and cytochrome c. The main function of the system is the coordinated transport of electrons and protons, which leads to the production of ATP.

This passage of electrons releases energy, which is largely stored in the form of a proton gradient across the inner mitochondrial membrane and is used by the last OXPHOS complex (F1Fo-ATPase) to generate ATP from ADP and inorganic phosphate.

Some of the ATP is used for the mitochondrion’s own needs, but most of it is transported outside the organelle by the adenine nucleotide translocator and used for diverse cell functions.

The OXPHOS system is unusual owing to its dual genetic control, which involves an interplay between the mitochondrial DNA and nuclear DNA.

 Nuclear genes of OXPHOS system

With only 13 OXPHOS polypeptides encoded by mtDNA, the bulk (at least 70) of the OXPHOS subunits are encoded by the nuclear genome. There are also several nuclear gene products that regulate mitochondrial gene expression.

Amost all of these genes have been characterized at the cDNA level and several at the genomic level in humans. In general, the chromosomal distribution of the genes seems to be random, and expression of most gene products is ubiquitous but predominates in tissues or organs with a high energy demand.
Richard Scarpulla and co-workers have provided important insight into the regulatory mechanisms that are involved in the transcriptional control of OXPHOS genes.

They identified the nuclear respiratory factors NRF1 and NRF2, which act on overlapping subsets of nuclear genes that are involved in the biogenesis of the respiratory chain.

 Analysis of the expression pattern of OXPHOS genes, both during liver development and in cancer cells, has indicated that regulation might also be exerted post-transcriptionally. Recent findings have indicated that the 3’-untranslated regions (3’-UTRs) of several essential nuclear-encoded components of the bioenergetic and replication/transcription machinery of rat kidney-cell mitochondria function as enhancers of translation.

Pathology of oxydative phosphorylation (OXPHOS)

Defects in the OXPHOS system (OXPHOS disease) result in devastating, mainly multisystem, diseases. Among the different groups of inborn errors of metabolism, mitochondrial disorders are the most frequent, with an estimated incidence of at least 1 in 10,000 live births. Although the terms "mitochondrial disorder" or "mitochobdrial diseases" are very broad, it usually refers to diseases that are caused by disturbances in the mitochondrial oxidative phosphorylation system (OXPHOS).

Whenever the clinical suspicion of a mitochondrial disorder arises, laboratory, electrophysiological and neuroradiological investigations are needed to justify more invasive procedures, such as muscle biopsy, which remains the mainstay of the diagnostic process. The key diagnostic features in muscle histochemistry are ragged red fibres (RRFs) and cytochrome c oxidase (COX) negative staining). Although intially described as a classic sign of mitochondrial disorders, other conditions such as exposure to certain drugs can also lead to these phenotypes.

Important examples of drugs that can cause a mitochondrial myopathy with RRFs in muscle are nucleoside analogues, such as zidovudine, used in the treatment of certain human immunodeficiencies. Nucleoside analogues, after conversion into their active form, inhibit mitochondrial DNA polymerase-gamma and induce mtDNA depletion.

Measurement of enzyme activities of the individual complexes of the OXPHOS system complete the diagnostic process. Both muscle histochemistry and enzymology have to be studied because isolated (one OXPHOS complex affected) and combined (more than one complex affected) deficiencies of the OXPHOS system can occur in the absence of RRFs and COX-negative phenotypes - predominantly a childhood phenomenon.

 Leigh syndrome has been associated with mitochondrial or nuclear mutations that cause defects at virtually every step of the OXPHOS system, but most commonly with isolated complex I or complex IV deficiency. Apart from Leigh syndrome, many other genetic disorders are now known to be caused by defects in the OXPHOS system. Among these are the classic mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and myoclonus epilepsy with ragged red fibres (MERRF), as well as some nuclear DNA mutation phenotypes such as deafness-dystonia syndrome (DDP). However, because of the genetic complexity of the energy-generating system, many other diseases have been shown to have an associated defect in mitochondrial function. For example, there is increasing evidence that inherited mitochondrial dysfunction underlies a significant fraction of cases of common, late-onset, heterogeneous disorders, such as diabetes and sensorineural hearing impairment.

Exemples

 Leigh syndrome
 mitochondrial encephalopathy
 lactic acidosis and stroke-like episodes (MELAS)
 myoclonus epilepsy with ragged red fibres (MERRF)
 deafness-dystonia syndrome (DDP)
 Parkinson disease susceptibility
 some diabetes mellitus
 some sensorineural hearing impairment

See also

 mitochondrial diseases

• OXPHOS diseases

References

 Shoubridge EA. Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet. 2001 Oct 1;10(20):2277-84. PMID: 11673411

 Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001 May;2(5):342-52. PMID: 11331900