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OXPHOS diseases

Thursday 27 January 2005

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 system).

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
- 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

Clinical syndromes

- Kearns-Sayre syndrome
- focal segmental glomerulosclerosis, hypoparathyroidism, sensorineural deafness, and progressive neurological disease (11470934)


- diabetes mellitus (10462141)

- renal anomalies

  • tubulopathies
    • de-Toni-Debre-Fanconi syndrome (8953126)


- OXPHOS diseases by faulty intergenomic communication

Diseases cab be caused by defective interplay between the mitochondrial and nuclear genomes.

MNGIE - The clinical features of the mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) include ophthalmoparesis, peripheral neuropathy, leukoencephalopathy and gastrointestinal symptoms (chronic diarrhea and intestinal dysmotility).

Muscle biopsy shows RRFs and COX-negative fibres and either partial isolated complex IV deficiency or combined OXPHOS-complex deficiencies. Mitochondrial DNA analysis in this autosomal recessive syndrome showed mtDNA deletions, depletion, or both.

The MNGIE locus was mapped to chromosome 22q13.32-qter, a region that contains the thymidine phosphorylase (TP) gene ECGF1.

Studies on patients showed that TP activity was markedly decreased, whereas the plasma thymidine levels were increased about 50-fold. Various homozygous as well as compound heterozygous ECGF1 mutations in the genomic DNA of MNGIE patients was found.

The precise mechanism by which TP deficiency leads to mtDNA rearrangements has still to be explained, but imbalance of the mitochondrial nucleotide pool is likely to have a role.

- ADPEO - Autosomal dominant progressive external ophtalmoplegia (ADPEO) is an adult-onset mitochondrial disorder that is characterized by progressive external ophthalmoplegia and variable additional features, including exercise intolerance, ataxia, depression, hypogonadism, hearing deficit, peripheral neuropathy and cataract.

Some patients carry mtDNA deletions, although the disease is inherited in an autosomal fashion. Of the two autosomal loci for this disorder, the 4q-adPEO locus includes the gene for the heart and skeletal muscle isoform of the adenine nucleotide translocator (ANT1).

ANT1 exchanges ATP for cytosolic ADP across the mitochondrial inner membrane and provides the cytosol with energy. Kaukonen et al.74 identified

Two heterozygous missense mutations in this gene have been identified in several families and in one sporadic patient with adPEO. Their results are in agreement with data obtained from a knockout mouse model of ANT1 deficiency and indicate that ANT1 has a role in mtDNA maintenance.

In contrast to other mitochondrial disorders that are caused by loss-of-function mutations in nuclear genes, this form of adPEO is caused by a dominant mechanism, which remains to be elucidated.

- OXPHOS assembly, homeostasis and import defects

Enzyme complex-I and complex-IV deficiencies are by far the most frequently observed abnormalities of the OXPHOS system. In sharp contrast to isolated complex-I deficiencies, no mutations have been found as yet in the ten nuclear genes that encode the structural proteins of complex-IV.

The discovery of mutations in a nuclear assembly gene that is associated with COX deficiency resulted from chromosomal transfer experiments, in which chromosomes can be identified that complement the mitochondrial defect in patient cell lines.

The inference is that the chromosome contains a functional copy of the gene that has been mutated in the patient. Once the chromosome has been identified, the gene is localized more precisely by introducing deleted versions of this chromosome.

Candidate genes can then be identified and tested for complementation on the basis of information from human and model organism genome projects. In particular, many yeast genes are already known to participate in the assembly of complex-IV, and human gene orthologues of these yeast genes have been identified.

The first success of this approach was the identification of mutations in the SURF1 (surfeit 1) gene in patients with COX-deficient Leigh syndrome.

- Nuclear gene defects that are associated with isolated complex-III deficiency or complex-V deficiency have not yet been discovered.

- Four inherited neurodegenerative diseases, Friedreich ataxia, hereditary spastic paraplegia, human DDP and dominant optic atrophy (OPA1) have also been shown to be mitochondrial disorders that are caused by nuclear DNA mutations in the genes for frataxin, paraplegin, DDP and OPA1, respectively.

- Friedreich ataxia and frataxin

Mitochondria obtained from heart biopsies of Friedreich ataxia patients have disclosed specific defects in the citric-acid cycle enzyme aconitase, and complex I-III activities.

The causative Friedreich ataxia protein, dubbed frataxin encoded by FRDA, has an essential role in mitochondrial iron homeostasis, and Friedreich ataxia can therefore be considered as an OXPHOS homeostasis defect.

- hereditary spastic paraplegia

Muscle biopsies from the autosomal recessive form of patients with hereditary spastic paraplegia revealed histochemical signs of a mitochondrial disorder, namely RRFs, COX-negative fibres and succinate dehydrogenase-positive hyperintense fibres.

Linkage and subsequent mutation analysis revealed large deletions in gene SPG7 encoding paraplegin.

Owing to the homology with a yeast mitochondrial ATPase with both proteolytic and chaperone-like activities, it has been suggested that this form of hereditary spastic paraplegia could be a neurodegenerative disorder due to OXPHOS deficiency, attributing a putative function in the assembly or import of respiratory chain subunits or cofactors to paraplegin.

- DDP syndrome

The DDP syndrome, an X-linked recessive disorder also known as the Mohr-Tranebjaerg syndrome, is associated with a novel defect in mitochondrial protein import. The defective gene is homologous to the yeast protein Tim8, which belongs to a family of proteins that are involved in intermembrane protein transport in mitochondria. Therefore, the DDP syndrome should be considered as the first example of a new group of mitochondrial import diseases.

- dominant optic atrophy (OPA1)

OPA1 is caused by defects in a dynamin-related protein that is targeted to mitochondria and might exert its function in mitochondrial biogenesis and in stabilization of mitochondrial membrane complexes.

- Clinical variability

The variability in clinical presentation of mitochondrial disorders is a recurring theme in the field. However, in the case of nuclear gene mutations, there is at least the following general correlation between genotype and disease: ECGF1, SURF1, SCO2 (cytochrome-oxidase-deficient homologue 2) DDP and OPA1 are involved in MNGIE, Leigh syndrome, cardioencephalomyopathy, deafness-dystonia syndrome and optic atrophy, respectively.

- Consequences of OXPHOS mutations

The consequences of OXPHOS defects affect various cellular properties, such as mitochondrial membrane potential, ATP/ADP ratio, ROS production and mitochondrial calcium homeostasis.

Theoretically, decreased proton pumping due to respiratory chain defects can result in reduced mitochondrial membrane potential and proton gradient, which are used to generate ATP.

There is a clear decrease in mitochondrial membrane potential in MERRF, as well as MELAS fibroblasts, in which mutations lead to a generally decreased mitochondrial protein synthesis, often resulting in a combined complex I and IV deficiency.

They also found evidence for a decreased ability to synthesize ATP and to maintain the ATP/ADP ratio in cells derived from MERRF and MELAS patients105. This is the first demonstration that cells containing mtDNA mutations are particularly sensitive to increased ATP demand.

Another important damage-inflicting mechanism that is possibly involved in some OXPHOS-system deficiencies is the abundant generation of ROS, the most prominent members of which are superoxide, hydrogen peroxide and the hydroxyl radical.

mtDNA isolated from complex-I-deficient fibroblasts of patients with cataract and cardiomyopathy contains many deletions in contrast to control fibroblasts, which indicates free oxygen radical damage.

Furthermore, they showed that the mitochondrial radical scavenger Mn-SOD levels were elevated in these patients.

Later results revealed a spectrum of abnormalities that ranged from elevated superoxide levels combined with reduced Mn-SOD values (in patients with cataract and developmental delay), to reduced superoxide levels with increased values of Mn-SOD (in patients with cataract and cardiomyopathy).

Measurement of superoxide production in control fibroblasts treated with the complex I inhibitor rotenone revealed increased superoxide production rates.

complex I deficiency could increase the formation of ROS, although variable induction of Mn-SOD influences this rate.

Other studies in complex-I-deficient cell lines have also shown increased hydroxyl radical production and overproduction of aldehydes, the latter indicative of lipid peroxidation.

Finally, there have been reports of altered cellular calcium handling in some mitochondrial disorders. A disturbance in mitochondrial Ca2+ homeostasis was shown in cells derived from the tRNA(Lys) mutation of MERRF syndrome.

Importantly, treatment of MERRF cells with a specific inhibitor of Ca2+ efflux, restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensuing stimulation of ATP production.

Overall, these results emphasize the differences in the cellular pathogenesis of the various mitochondrial DNA defects.

By organs

- OXPHOS liver diseases
- OXPHOS myopathies
- OXPHOS cardiomyopathies


- 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

- Di Mauro S, Schon EA: Mitochondrial respiratory-chain diseases. New Engl J Med 348:2656, 2003.