Biology of Disease

They are associated not only with numerous mutations of the mtDNA

but also mutations in nuclear genes that affect processes such as the

assembly of protein subunits and the import of proteins from the cytosol

into the mitochondrion. Such mutations can affect the morphology of the

mitochondrion (Figure 16.8).

Mitochondria replicate by simple divisions that are independent of mitosis

and meiosis. The mitochondrial chromosomes are copied prior to replication.

However, the replicating enzyme, mtDNA-dependent DNA polymerase or

DNA polymerase F, replicates DNA with much poorer fidelity than the nuclear

DNA polymerases. Thus the mutation rates of mitochondrial genes are esti-

mated to be about 10 times greater than those of nuclear genes. This may

contribute to the aging process (Chapter 18). Furthermore, the mitochondrial

genome resembles that of bacteria in that the genes lack introns and repeated

DNA sequences so that about 93% of the DNA is transcribed as opposed to

the 5% or less for the nuclear genome. Thus, despite its relatively small size,

a relatively large number of mutations are associated with mtDNA and these

mutations are significant contributors to human disease.

Mitochondrial disorders are caused by similar types of mutations to those

that cause diseases associated with the nuclear genome, that is, point muta-

tions, deletions, and duplications (Chapter 15). However, the inheritance

of these diseases differs strikingly to that of the nuclear genetic diseases. In

zygote formation, a spermatozoon contributes its nuclear genome but not its

mitochondrial genome to the egg cell. The resulting fertilized zygote contains

only the mitochondria that were present in the unfertilized egg and are there-

fore entirely maternal in origin. Thus all children, male and female, inherit

their mitochondria only from their mother, and males cannot transmit their

mitochondria to subsequent generations (Figure 16.9). Thus a typical disease

resulting from a mutation in mtDNA is an inherited condition that can affect

both sexes but can only be passed on by affected mothers.

The first disease to be directly linked to mutations in mtDNA was Leber

hereditary optic neuropathy (LHON), an inherited neuropathology. This

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Transfer RNA

Complex III

Complex I

Complex IV

Complex V

Ribosomal RNA

16S

rRNA

12S

rRNA

LHON

LHON

LHON

MERRFNARP

LHON

MELAS

DEAF

D-loop

ADPD

Figure 16.7 Schematic of

a human mtDNA molecule

showing its major regions

and the sites of mutations

associated with some

mitochondrial disorders (see

Table 16.3).This diagram was

compiled from several sources.

0.6 μm

Figure 16.8 Electron micrograph showing

abnormal morphology of a mitochondrion

associated with a mitochondrial disorder.

Compare with Figure 16.6.Courtesy of M.J.

Cullen, Muscular Dystrophy Research Laboratories,

Newcastle General Hospital, UK.

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