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The genetics and pathology of oxidative phosphorylation

Key Points

  • Defects in the oxidative phosphorylation (OXPHOS) system — the final biochemical pathway in the production of ATP — result in devastating, mainly multisystem diseases.

  • The OXPHOS system is under dual genetic control, which involves an interplay between the mitochondrial and the nuclear genomes.

  • Maternal inheritance, polyplasmy, heteroplasmy and the threshold effect are the fundamental differences between mitochondrial and Mendelian genetics.

  • In the past 13 years, more than 100 point mutations and innumerable rearrangements of mitochondrial DNA (mtDNA) have been associated with human mitochondrial disease.

  • In the past five years, nuclear DNA mutations have been found in genes that affect several aspects of OXPHOS function: structural OXPHOS genes, intergenomic communication, OXPHOS-complex assembly, import and energy homeostasis.

  • Progress in this field has greatly benefited from the human genome project and from knowledge obtained from lower species.

  • Recent technical advances in mouse mitochondrial genetics have enabled numerous OXPHOS disease models to be created, which has considerably increased our insight into the pathophysiology of these diseases.

Abstract

The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway in the production of ATP. The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome. Defects in the OXPHOS system result in devastating, mainly multisystem, diseases, and recent years have seen the description of the underlying genetic mutations in mitochondrial and nuclear genes. Advances in this arena have profited from progress in various genome projects, as well as improvements in our ability to create relevant animal models.

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Figure 1: OXPHOS system in mammalian mitochondria.

Animated online

Figure 2: The mitochondrial genome.
Figure 3: Mitochondrial transcription and translation.
Figure 4: Muscle phenotypes of OXPHOS disorders.
Figure 5: Classification of OXPHOS disorders.
Figure 6: Chromosome transfer technique.

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Acknowledgements

First, we would like to express our gratitude to all patients and their parents: without their collaboration, progress in our understanding of OXPHOS-system disorders would not have been possible. We thank R. Sengers and F. Trijbels, founders of the Nijmegen Centre for Mitochondrial Disorders, for their continuous support; M. Coenen for help in preparing figure 6; and L. Grivell for his critical reading of the manuscript. Part of this work was supported by the Prinses Beatrix Fonds, the Dutch Scientific Organisation, the National Institutes of Health, and the Muscular Dystrophy Association.

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DATABASE LINKS

Leigh syndrome

MELAS

MERRF

deafness–dystonia syndrome

LHON

ND1

ND4

ND6

isolated complex II deficiency

Leigh-like presentation

NDUFS4

NDUFS7

NDUFS8

MNGIE

ECGF1

adPEO

ANT1

SURF1

COX-deficient Leigh syndrome

Friedreich ataxia

OPA1

frataxin

paraplegin

SCO2

Sod2

Ant1

Tfam

MTIF2

FURTHER INFORMATION

Mitomap

Neuromuscular mitochondrial disorders

Nijmegen Centre for Mitochondrial Disorders

The Mitochondrial Medicine Society

MitoPick — information about complex I

Takao Yagi's lab

Yeast Proteome Database

The Children's/European Mitochondrial Disease Network C/EMDN

Glossary

POLYPLASMY

The presence of many copies of mitochondrial DNA in each cell.

HETEROPLASMY

The coexistence of wild-type and mutated mitochondrial DNA in the same cell.

RESPIRATORY CHAIN

The functional supramolecular structure located in the inner mitochondrial membrane and composed of the first four complexes of the OXPHOS system.

ENCEPHALOPATHY

A term generally used to describe the cerebral pathology of grey and/or white matter.

OPHTHALMOPARESIS

Paralysis of the eye muscles without involvement of the upper eyelids.

HYPOTONIA

A clinical diagnosis indicated by diminished resistance to passive movements (such as bending of the knee by the investigator) and an excessive range of joint mobility.

ATAXIA

Inability to coordinate movement.

DYSTONIA

Sustained simultaneous contraction of agonist and antagonist muscles, resulting in unusual postures that are transiently maintained.

ENCEPHALITIS

Inflammation of the brain.

INTERCURRENT ILLNESS

An illness unrelated to the primary disease (for example, infection).

MUTATIONAL LOAD

A measure of the proportion of mutated DNA — for example, the degree of heteroplasmy for a mitochondrial DNA mutation.

CYBRID

A cytoplasmic hybrid cell line, usually generated by fusing rho0 cells with cells from patients harbouring mitochondria.

RHO0 CELLS

Cell lines that are entirely lacking mitochondrial DNA, usually as a result of exposure to ethidium bromide.

LEUCOENCEPHALOPATHY

General term to describe a disease of the cerebral white matter.

PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA

(PEO). Progressive paralysis of the muscles that move the eyes in the orbit and elevate the eyelids.

CONDITIONAL KNOCKOUT

In mice, conditional knockouts are made by inserting loxP sites on either side of the gene to be inactivated. Expression of the Cre recombinase then deletes the interval between the loxP sites. Tissue-specific expression of Cre makes organ- or tissue-specific disruptions of the target gene possible.

DIFFERENTIAL DISPLAY

A gel-based technique to survey genome-wide levels of transcription.

SYNAPTOSOMES

Resealed cytoplasmic vesicles from nerve endings that contain (mutated) mitochondria.

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Smeitink, J., van den Heuvel, L. & DiMauro, S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2, 342–352 (2001). https://doi.org/10.1038/35072063

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