chapter 14
Electron Transport and Oxidative Phosphorylation
TABLE 14-7
Correlations Found between Mitochondrial DNA Mutations and Human Diseases*
A. Nucleotide Substitutions
Clinical Features
1. Mildly deleterious base substitutions
2. Moderately deleterious nucleotide substitutions
3. Severe nucleotide substitutions
Familial deafness, Alzheimer’s disease, Parkinson’s disease
Leber’s Hereditary Optic Neuropathy (LHON), Myoclonic
Epilepsy and Ragged-Red Fiber disease (MERRF)
Leigh’s Syndrome dystonia
B. (mt)DNA Rearrangements
1. Milder rearrangements (duplications)
2. Severe rearrangements (deletions)
Maternally inherited adult-onset diabetes and deafness
Adult-onset, Chronic Progressive External Ophthalmoplegia
(CPEO), Keams-Sayre Syndrome (KSS), Lethal Childhood
Disorders, Pearsons Marrow/Pancreas Syndrome
♦Modified from D. C. Wallace
J. o f B io e n e r g e tic s a n d B io m e m b r a n e s
26 (1994) 241-250.
A number of nuclear-derived transcription factors has
been implicated in respiratory chain expression and may
play an important role in control of mitochondrial func-
tions. One nuclear respiratory factor (NRF-1) binds to
genes encoding respiratory proteins, to the rate-limiting
enzyme in heme biosynthesis, and to components of
mtDNA transcription and replication. A second respira-
tory factor (NRF-2) is required for maximal production
of cytochrome c oxidase subunit IV (COXIV)
Vb (COXVb). The two regulatory proteins act on a subset
of overlapping nuclear genes required for mitochondrial
respiratory activity and integrate the expression of nuclear
and mitochondrial genes. Complexes III, IV, V, and cy-
tochrome c have at least one subunit whose expression is
under NRF control. Another regulatory protein (mtTFA)
stimulates transcription initiated by mitochondrial RNA
polymerase from heavy (H) and light (L) strand promot-
ers within the mtDNA D-loop. The essential role of mtTFA
in the transcription and maintenance of mtDNA makes it
a prime candidate for a regulatory function in nuclear-
mitochondrial interactions.
of mitochondrial
mitochondrial termination factor TERF promotes termina-
in vitro.
The factor binds at the junction between 16S
rRNA and leucyl-tRNA genes, a bidirectional termi-
nation site. The binding activity is associated with a
34-kDa protein. A point mutation associated with mito-
chondrial myopathy, encephalomyopathy, lactic acidosis
and stroke-like episodes diminishes the termination of 16S
rRNA transcription
in vitro
and reduces the binding affin-
ity of the 34-kDa protein. These findings suggest a poten-
tial link between human disease and a nDNA regulatory
14.6 Mitochondrial Diseases
The bioenergetic defects resulting from mtDNA muta-
tions may be a common cause of degenerative diseases
(Table 14-7). Defects in nuclear-cytoplasmic interaction
are generally the resultant of autosomal dominant mu-
tations; complex disease states result from depletion of
mtDNAs from tissues. Mitochondrial DNA mutations are
associated with a broad spectrum of chronic degenerative
diseases with a variety of clinical presentations. Identical
mutations are associated with very different phenotypes
and the same phenotype can be associated with different
Base Substitution Mutations
Diseases involving mtDNA nucleotide substitution rep-
resent a broad array of clinical phenotypes typically
featuring nervous system involvement. LHON (
hereditary optic neuropathy),
the best studied mtDNA nu-
cleotide substitution disease, is characterized by a rapid,
painless, bilateral loss of central vision due to optic nerve
atrophy. The disease is maternally inherited, and its occur-
rence within families is variable, with young adult males
most commonly affected. Modulating factors also influ-
ence disease expression. LHON is a genetically heteroge-
neous disease associated with at least 16 different missense
mutations in mtDNA. Three of these—ND1 gene, ND4
gene, and ND
gene—are the primary causes of LHON.
The latter mutation is believed to cause not only LHON
but also childhood dystonia associated with bilateral basal
ganglia degeneration (LHON + dystonia).
Two heteroplasmic missense mutations (ATPase G
gene) result in highly variable disease phenotypes within
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