Mitochondrial Disorders


Mitochondria are double‐membrane organelles which play a pivotal role in cellular metabolism and are responsible for creating free energy, in the form of ATP, essential for the normal function and maintenance of all human organ systems. Genetic defects of mitochondrial functions cause human diseases associated with a wide spectrum of clinical phenotypes.

Keywords: oxidative phosphorylation; respiratory chain defects; mitochondrial deoxyribonucleic acid; maternal inheritance; nuclear‐encoded mitochondrial proteins

Figure 1.

Mitochondrial structure and function. Mitochondria play an essential role in many aspects of cellular metabolism, but their primary function is the synthesis of adenosine triphosphate (ATP) via the pathways of oxidative phosphorylation. Mitochondria contain two different membranes, the outer and the inner membrane, which are separated by the intermembrane space. The surface area of the inner membrane is greatly increased by a large number of infoldings (cristae), which protrude into the matrix space. The outer membrane contains pore proteins that render it permeable for ions and small molecules. The inner membrane is impermeable and has a very high protein content. It contains the multisubunit complexes comprising the oxidative phosphorylation (OXPHOS) system, as well as various carrier proteins, such as the ATP/adenosine diphosphate (ADP) carrier, which mediate the transport of metabolites in and out of the matrix space. The matrix space is the site of the Krebs cycle, the pyruvate dehydrogenase complex and the enzymes of β‐oxidation. Matrix proteins also comprise enzymes involved in synthesis or metabolism of amino acids, ketones, urea, pyrimidines, nucleotides and heme. OM: outer membrane; IM: inner membrane; IMS: intermembrane space.

Figure 2.

Mitochondrial OXPHOS system. The respiratory chain consists of four high molecular weight complexes (I–IV). Complexes I, III and IV act as proton pumps, generating an electrochemical gradient across the inner membrane, which is then used by the F1F0–ATPase complex (complex V) to generate ATP from ADP and phosphate. Both the nuclear and the mitochondrial genome contribute to the biogenesis of these complexes in the mitochondrial inner membrane. Only complex II is made exclusively by nuclear‐encoded polypeptide chains. The number of subunits contributed by the nuclear genome and mitochondrial genome are shown. Q: coenzyme Q; C: cytochrome c.

Figure 3.

Human mitochondrial genome. The mitochondrial DNA (mtDNA) is a 16569‐bp‐long, circular, double‐stranded molecule. It contains 37 genes, which encode the RNA components of the mitochondrial translational apparatus, that is, the 22 transfer RNA (tRNA) and two ribosomal RNA (rRNA) species (12S rRNA, 16S rRNA), as well as 13 polypeptides, all of which are essential subunits of the OXPHOS complexes. The mtDNA is compact; it contains no introns and only one noncoding region of significant length, the ‘displacement loop’ (D‐loop), which harbors the origin of replication of the heavy (H)‐strand. The origin of replication of the light (L)‐strand is located downstream at two‐thirds of the mtDNA length. Replication of the mtDNA occurs independent of the cell‐cycle phase and from replication of the nuclear DNA. Synthesis of each mtDNA strand thereby proceeds asynchronously from the two separate origins of replication. Both mtDNA strands are transcribed as polycistronic RNAs from their own promoters. To release functional RNA species (rRNA, tRNA, (mRNA)), these primary transcripts are processed by cleavage and modification. OH and OL: origins of H‐ and L‐strand replication; HSP1 and HSP2: H‐strand promoters; LSP: L‐strand promoter; ND (‐1, ‐2, ‐3, ‐4, ‐4L, ‐5, ‐6): genes for complex I reduced nicotinamide adenine dinucleotide (NADH) subunits; Cyt b: cytochrome b gene (complex III); COX (I, II, III): complex IV subunit genes; ATP (‐6, ‐8): complex V subunit genes. Arrows: directions of DNA and RNA synthesis. See also Disease-related Genes: Functional Analysis


Further Reading

Bauer MF, Gempel K, Jaksch M, et al. (1999) Mitochondrial disorders: a diagnostic challenge in clinical chemistry. Clinical and Chemical Laboratory Medicine 37: 855–876.

Bauer MF, Hofmann S, Neupert W and Brunner M (2000) Protein translocation in mitochondria: the role of Tim proteins. Trends in Cell Biology 10: 25–31.

Frey TG and Mannella CA (2000) The internal structure of mitochondria. Trends in Biochemical Science 25: 319–324.

Maechler P and Wollheim CB (2001) Mitochondrial function in normal and diabetic beta‐cells. Nature 414: 807–812.

Patel PI and Isaya G (2001) Friedreich ataxia: from GAA triplet‐repeat expansion to frataxin deficiency. American Journal of Human Genetics 69: 15–24.

Shoubridge EA (2001) Nuclear genetic defects of oxidative phosphorylation. Human Molecular Genetics 10: 2277–2284.

Smeitink J, van den Heuvel L and DiMauro S (2001) The genetics and pathology of oxidative phosphorylation. Nature Reviews Genetics 2: 342–350.

Suomalainen A and Kaukonen J (2001) Disease caused by nuclear genes affecting mtDNA stability. American Journal of Medical Genetics 106: 53–61.

Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283: 1482–1497.

Web Links

MITOMAP: A Human Mitochondrial Genome Database. The database comprises a compendium of polymorphisms and mutations of the human mitochondrial DNA. Clinical phenotypes and functional descriptions are provided via useful links on the Web

MITOP: Database for mitochondria‐related genes, proteins and diseases. MITOP project is supported by a German Human Genome Project and combines all relevant information concerning genetic, functional and human‐pathological aspects of the central role of mitochondria in the organism, with an emphasis on nuclear encoded proteins

MitoNet: This is a network of competence gathering physicians and scientists in order to improve research, diagnostics and therapy on/of ‘mitochondrial disorders’. MitoNet gives general information on mitochondrial disorders, supports specific patient groups, offers the expert knowledge to the medical society and supports the collaboration between clinic and research

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How to Cite close
Hofmann, Sabine, and Bauer, Matthias F(Jan 2006) Mitochondrial Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005539]