Mitochondrial DNA and Diseases


The mitochondrial genome (mtDNA, mitochondrial deoxyribonucleic acid) is an essential source of extranuclear DNA in mammalian cells, located in the matrix of the organelle. It is much smaller than chromosomal DNA (only 16 569 bp) but thousands of copies per nucleated cell are found in nucleoprotein complexes termed nucleoids, which may constitute the heritable unit. mtDNA is maternally inherited and encodes 13 polypeptides, all fundamental for coupling cellular respiration to ATP (adenosine triphosphate) production. Consequently, mutated mtDNA can cause profound cellular dysfunction and death. Many pathogenic mtDNA mutations are known: single point mutations and rearrangements underlie clinical disorders known as mitochondrial cytopathies or encephalomyopathies; several nuclear gene mutations are known to cause mtDNA rearrangements; there exists an association between mtDNA deletions and the ageing process. Models explain how deletions may occur, but it is unknown how these deleted molecules predominate in individual cells over time, a process termed clonal expansion.

Keywords: mitochondrial DNA; mitochondrial disease; heteroplasmy; homoplasmy

Figure 1.

Schematic representation of the human mitochondrial genome. The human mitochondrial genome is a circular, closed, covalent molecule of 16 569 bp. The two strands are represented here, the inner being the light (L) strand and the outer the heavy (H) strand. The positions of the (rRNAs), protein coding regions and the punctuating (tRNAs), shown as small blue circles, are indicated on the appropriate strands. Both of the two heavy and one light strand promoters (HSP1/2 and LSP) are located within the noncoding region. There is substantial current debate about the exact origins of mtDNA replication.

Figure 2.

Schematic of the mitochondrial respiratory chain components. The process of oxidative phosphorylation couples electron transfer and proton pumping. The five complexes involved are represented in this diagram, together with the electron carriers ubiquinol (Q) and cytochrome c (C). Complexes I, III, IV and V comprise polypeptides encoded by both the nuclear and the mitochondrial genome. In total, the human mitochondrial genome encodes 13 polypeptides, all of which are members of the respiratory chain: 7 of complex I, 1 of complex III, 3 of complex IV and 2 of complex V. FAD, flavin–adenine dinucleotide; NAD, nicotinamide–adenine dinucleotide; ADP, adenosine diphosphate; Pi, inorganic phosphate and ATP, adenosine triphosphate.



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Further Reading

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Boesch, Pierre, Lightowlers, Robert N, and Chrzanowska‐Lightowlers, Zofia MA(Dec 2008) Mitochondrial DNA and Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001462.pub2]