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doi: 10.1093/abbs/gmn021. |
Pathogenic mutations
of nuclear genes associated with mitochondrial disorders
Xiaoyu
Zhu1, Xuerui Peng1, Min-Xin Guan2, and
Qingfeng Yan1*
1College of Life Science,
and Program in Human Genetics,
address: Tel/Fax: t86-571-88206646; E-mail: [email protected]
Mitochondrial
disorders are clinical phenotypes associated with mitochondrial dysfunction,
which can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes.
In this review, we summarized the pathogenic mutations of nuclear genes
associated with mitochondrial disorders. These nuclear genes encode,
components of mitochondrial translational machinery and structural subunits and
assembly factors of the oxidative phosphorylation, that complex. The molecular
mechanisms, that nuclear modifier genes modulate the phenotypic expression of
mtDNA mutations, are discussed in detail.
Keywords
mitochondria; mitochondrial disorder;
nuclear modifier gene; pathogenic mutation
Received:
October 7, 2008 Accepted: November 25, 2008
Introduction
Mitochondrial
disorders are clinical phenotypes associated with mitochondrial dysfunction, in
particular, abnormalities of oxidative phosphorylation (OXPHOS), which can be
caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes. When
combining the results of the epidemiology data on childhood and adult
mitochondrial diseases, the minimum prevalence is at least
Pathogenic
Mutations of Nuclear Genes Encoding OXPHOS Complex Structural Subunits
Mitochondrial
proteome is estimated to consist of approximately 1500 gene products.
Mitochondrial genome encodes only 13 essential polypeptides of OXPHOS, whereas
all other structural subunits and assembly factors are nuclear-encoded and
imported into mitochondria. The OXPHOS system is composed of five complexes,
four of which, complexes I–IV,
cooperate to generate a proton gradient across the mitochondrial inner
membrane. Complex V generates the universal energy ATP coupling with proton
flow [7]. In the past few years, a number of pathogenic mutations in
OXPHOS-related nuclear genes have been identified. Mutations of nuclear-encoded
structural subunits were summarized in Table 1. Complex I (NADH-ubiquinone
reductase) catalyzes the first step in the mitochondrial respiratory chain, in
which transfer of electrons from NADH to ubiquinone (co-enzyme Q) is accompanied
by the translocation of protons across the inner mitochondrial membrane.
Complex I is composed of at least 46 subunits, in
which seven are encoded by mtDNA and the others by nuclear DNA, whose
deficiency is the most common cause of the mitochondrial disease.
Nuclear-encoded subunits are termed NADH dehydrogenase ubiquinone (NDU),
followed by a description of function/location (FS-iron-sulfur protein region,
FV-flavoprotein region, FA-subcomplex a, FB-subcomplex b, FC-undefined
subcomplex). Complex I deficiency causes a wide range of clinical disorders,
ranging from neurological disorders, such as Leigh’s syndrome (LS), to
cardiomyopathy, liver failure, or myopathy [8,9].
Pathogenic mutations have now been described in 12 of the nuclear-encoded structural
subunits (NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1,
NDUFV2, NDUFA1, NDUFA2, and NDUFA11) [10221] of complex I. Mutations of seven
of these nuclear genes (NDUFS1, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, and
NDUFA2) [10,12,13,15,16,20] result in Leigh or Leigh-like syndromes, whereas
mutations of the NDUFS2 [11], NDUFS6 [14], NDUFV2 [18], NDUFA1 [19], and
NDUFA11 [21] genes are associated with hypertrophic cardiomyopathy and
encephalomyopathy. NDUFS4 and NDUFS6 are both located in the iron–sulfur fraction of complex I, whose mutations
can either prevent complete assembly or destabilize the peripheral arm; the
other seven nuclear-encoded subunits (NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8,
NDUFV1, and NDUFV2) [15–18]
are constitutive of the core of complex I, considered to be essential for the
catalysis of electron transfer from NADH to ubiquinone, and for the generation
of the proton motive force. Recently, Fernandez-Moreira et al. [19] identified
a hemizygous mutation in the X-linked gene NDUFA1, resulting in the
assembly/stability abnormalities in the mitochondrial respiratory complexes.
Hoefs et al. [20] identified a homozygous G-to-A transition in intron 2 of the
NDUFA2 gene, resulting in the skipping of exon 2 and generation of a
prematurely truncated protein. Further studies showed that the NDUFA2 mutation
resulted in the disturbed assembly and stability of complex I and decreased
complex I activity. A splice-site mutation in the NDUFA11 gene is predicted to
abolish the first transmembrane domain of the gene product, thereby
destabilizing the enzymatic complex [21]. Complex II (succinate-cytochrome c
reductase) is an FAD-dependent enzyme at a cross-point between OXPHOS and
Krebs-cycle pathways. It comprised four protein subunits encoded by nuclear
genes (SDHA, B, C, and D). The homozygous SDHA (flavoprotein subunit) mutations
are associated with LS [5], whereas heterozygous mutations in SDHB [22] (iron–sulfur subunit) and in both SDHC [23] and
SDHD [24] (integral membrane-protein subunits) are associated with
paraganglioma. Complex III (ubiquinol cytochrome c reductase) catalyzes
electron transfer from succinate and nicotinamide adenine dinucleotide-linked
dehydrogenases to cytochrome c. It is made up of 11 subunits, of which all but
one (cytochrome b) are encoded by nuclear DNA. Haut et al. [25] reported a
deletion in UQCRB, encoding the human ubiquinone-cytochrome c reductase binding
protein of complex III (QP-C subunit), in a consanguineous family with
hypoglycemia and lactic acidosis. Barel et al. [26] identified a single
missense (Ser45Phe) mutation in UQCRQ, encoding a ubiquinone-binding protein of
low molecular mass, from a large consanguineous
Israeli Bedouin kindred with an autosomalrecessive syndrome comprising severe
psychomotor retardation and extrapyramidal signs. Complex IV (cytochrome c
oxidase, COX) is the terminal complex of the electron transport chain, which
transfers electrons from cytochrome c to molecular oxygen and contributes to
the proton motive force used in the generation of ATP. Complex IV is composed
of 13 subunits, in which the three largest ones are encoded by mtDNA, whereas
the remaining subunits are encoded by nuclear genes. The mtDNA-encoded subunits
function during electron transfer, and the nuclear-encoded subunits may be
involved in the regulation and assembly of the complex. Massa et al. [27] first
reported a disease-associated nuclear gene mutation in COX6B1, which encodes
cytochrome c oxidase subunit Vib polypeptide 1 (ubiquitous), resulting in severe
infantile encephalomyopathy. Complex V (ATP synthase or ATPase) couples proton
flow from the inter-membrane space back to the matrix by the conversion of ADP
and inorganic phosphate to ATP. ATP synthase comprises an integral membrane
component F0 and a peripheral moiety F1. It comprised at least 14
nuclear-encoded subunits and two mtDNAencoded subunits. Up to now, mutations of
nuclearencoded structural subunits were sought for, but never been found in
complex V-defective patients.
Pathogenic
Mutations of Nuclear Genes Encoding OXPHOS Complex Assembly Factors
Although
many mutations in nuclear-encoded structural subunits have been identified,
they account for only a minority of the OXPHOS complex deficiency cases. The
fact suggests that the molecular cause of the disease should be found in other
factors involved in the catalytic regulation, assembly, or maintenance of the
complex. Only in recent years, a number of assembly factors have been
validated, as summarized in Table 2. The role of such factors in complex I
biogenesis includes involvement in subunit maturation (e.g. folding/ co-factor
attachment), chaperoning intermediate assemblies, subunit synthesis, and
turnover. B
Pathogenic
Mutations of Nuclear Genes Encoding Mitochondrial Translational Machinery
Mitochondria
contain a separate translational machinery to produce the mtDNA-encoded
polypeptides using mtDNA-encoded tRNA. rRNA encoded by
the mtDNA is combined with nuclear-coded proteins to generate mitochondrial
ribosomes (mitoribosomes), which is composed of two subunits: the small subunit
(SSU) consists of the 12S rRNA and 29 proteins and the large subunit consists
of the 16S rRNA and 48 proteins. Synthesis of mitochondrial proteins requires a
number of initiation, elongation, and termination (or release) factors and
enzymes for mitochondrial rRNA and tRNA maturation (RNA processing and
base-modification), all of which are encoded by nuclear genes [42]. Initial
factor IF2 promotes the binding of formyl methionyl-transfer RNA (fMet-tRNA) to
the small ribosomal subunit in the presence of guanosine triphosphate (GTP) and
a template, whereas IF3 promotes the dissociation of the two ribosomal
subunits, which produces free SSUs for the initiation of translation. The
mammalian elongation factor Tu participates in the formation of the ternary
complex that includes EFTu, GTP, and aminoacyl-tRNA, which delivers the
aminoacyl-tRNA to the acceptor site of the ribosome. The energy required for
this process is supplied by the hydrolysis of GTP, which is followed by the
release of EFTu from the ribosome as an EFTu-guanosine diphosphate (GDP)
complex. The exchange of GDP for GTP, which regenerates EFTu-GTP, is
accomplished by EFTs. EFG catalyzes the translocation of peptidyl-tRNA from the
ribosomal-acceptor site to the peptidyl site after peptidebond formation.
Concomitant movement of mRNA exposes the next codon in the acceptor site.
Release factor RF1 recognizes stop codons and promotes the releases of the
completed protein chain [43]. Several mutations in nuclear genes influencing mitochondrial
translational machinery have been identified, as summarized in Table 3. MRPS16
encodes a protein of the mitoribosomal SSU. The MRPS16 protein is located in a
narrow crevice on the SSU and has many contacts with the rRNA, being surrounded
by about five rRNA double helices. The binding of the Thermus thermophilus
ribosomal protein S16 is an important step in the assembly of the SSU of this
organism. A homozygous mutation C331T of MRPS16, predicting a premature stop
codon Arg111Ter, was identified in one infant with severe lactic acidosis,
developmental defects in the brain, and facial dysmorphisms [44]. MRPS22
encodes a mitochondrial ribosomal protein S22. A mutation in the MRPS22 gene
was identified, leading to a reduction of 12S rRNA in fibroblasts, from
patients with fatal neonatal hypertrophic cardiomyopathy and kidney tubulopathy
[45]. PUS1 (pseudouridine synthase 1) converts uridine into pseudouridine in
several positions of tRNAs synthesized in both nuclear
and mitochondrial compartments. A homozygous missense mutation of PUS1 was
identified in Persian Jewish families affected by myopathy, lactic acidosis,
and sideroblastic anemia. The amino acid change (Arg656Try) appears to be in
the catalytic center of the protein PUS1p [46,47].
EFTu (elongation factor Tu) brings aminoacylated transfer RNAs to the ribosomal
A site as a ternary complex with guanosine
triphosphate. EFTs (elongation factor Ts) functions as a guanine nucleotide
exchange factor for EFTu. The first mutation of EFTu was identified in a
patient with a severe infantile macrocystic leukodystrophy with micropolygyria
[48]. A homozygous mutation (C997T) of EFTs was found in patients with
hypertrophic cardiomyopathy [49]. Antonicka et al. investigated the tissue
specificity in patients with fatal hepatopathy due to EFG1 mutations. Liver was
the most severely affected tissue, with ,10% residual
assembly of complexes I and IV and a 50% decrease in complex V. Skeletal muscle
showed a 50% reduction in complex I, and complexes IV and V were 20% of the
control. In fibroblasts, complexes I and IV were 20% of the control, and there
was a 40–60% reduction in complexes III and
V. In contrast, except for a 50% decrease in complex IV, all other complexes
were nearly normal in the heart [50].
Nuclear
Modifier Genes Modulate the Phenotypic Expression of mtDNA Mutations
mtDNA
mutations are responsible for a number of maternally inherited diseases, but
not sufficient to account for the variable penetrance, implying that there must
be some modifiers involved. These reasonable modifiers include mtDNA haplotype
background, environmental factor, and nuclear modifier gene. The nuclear
modifier does not induce any pathology per se, but it contributes to the
pathogenic effect of the mitochondrial mutation. The nuclear modifier could be
a common functional polymorphism in a tissue-specific protein, possibly with
mitochondrial location [51]. In 1993, Prezant et al. [52] found that a
homoplasmic mtDNA A
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