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Mitochondrial DNA Mutations and Diseases
Lee-Jun C. Wong, Ph D, FACMG
Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas
Mitochondria are animal cellular organelles whose major function is to utilize the
molecular oxygen to convert the chemical energy in sugars and fatty acids into ATP, the
cellular energy currency. This process is called oxidative phosphorylation (OXPHOS),
in which, the NADH and FADH2 produced through TCA cycle and fatty acid betaoxidation in mitochondria are oxidized. Electrons from these reducing agents are going
through the electron transport chain and finally given to oxygen, creating a protongradient, which drives ATP synthesis. Most patients with mitochondrial disorders have
molecular defects affecting the mitochondrial OXPHOS system, consisting of ~ 87
protein subunits, forming five multi-protein complexes (complex I to V) embedded in the
inner mitochondrial membrane. Among these 87 proteins, 13 are encoded by the
mitochondrial genome and the remaining are encoded by the nuclear genome.
Mitochondrial disorders are a group of the most clinically and genetically
heterogeneous diseases known to date. Two genomes are involved, the tiny 16,569 bp
circular double stranded mitochondrial DNA (mtDNA) and approximately 1,500 nuclear
genes related to mitochondrial structure and function. Most human cells contain
hundreds to thousands of mitochondria, each of which contains multiple copies of
mtDNA(1). The human mitochondrial genome is a circular, double-stranded, 16.6 kb
DNA encoding 13 protein subunits of OXPHOS complexes, as well as 2 ribosomal
RNAs and 22 tRNAs essential for mitochondrial protein synthesis. With few exceptions,
all animal mitochondrial genomes share identical arrangement of the same 37 genes.
Unlike nuclear genes, mitochondrial DNA has the characteristics of (a) maternal
inheritance, (b) high mutation rate, (c) heteroplasmy, (d) random segregation, and (e)
threshold effect. Since mitochondria are present in every cell, mutations in mtDNA can
potentially affect all types of organ systems. Thus, mitochondrial disease often appears
as a multisystem disorder. However, tissues of high energy demand, such as nerve
and muscle are preferentially affected. Consequently, diseases involving central
nervous system, skeletal muscle, heart, neurosensory organs such as ears and eyes,
predominate the clinical features of the disorder. Clinical phenotypes of the affected
patients depend on the biochemical and molecular characteristics of the specific
mutation and its tissue distribution.
Since mitochondrial proteins are encoded by both the nuclear and mitochondrial
DNA, mitochondrial disorders can result from primary mutations in either genome.
Mitochondrial disorders caused by mutations in nuclear-encoded proteins are usually
autosomal recessive diseases with severe early childhood onset. In contrast, primary
mtDNA mutations result in milder disease with later onset. MtDNA point mutations that
are present in blood are often maternally inherited in that the same mutation can be
found in the mother and possibly in other matrilineal relatives. Depending on the
degree of mutation heteroplasmy and its tissue distribution, clinical phenotype varies.
Somatic/sporadic mtDNA mutations may occur in any tissue. For example, some cases
with mitochondrial myopathy and exercise intolerance may have mtDNA mutations in
muscle only. Therefore, the absence of mtDNA mutations in blood sample does not
always rule out the diagnosis of mitochondrial DNA disorders. There are some common
mtDNA point mutations and deletions with classical, recognizable syndromes, including
MELAS, MERRF, NARP, Leigh disease, LHON, Pearson syndrome and Kearnes Sayre
syndrome. Mitochondrial myopathy due to mtDNA multiple deletions may be secondary
to primary mutations in nuclear genes responsible for the maintenance of mtDNA
integrity. In addition to qualitative changes in mtDNA, there are quantitative changes in
mtDNA copy number, known as mtDNA depletion or mtDNA over-amplification. The
over-amplification of mtDNA is usually a compensatory mechanism for reduced
mitochondrial function, while mtDNA depletion is caused by genetic defects in one of a
group of nuclear genes involving mtDNA biosynthesis, which is usually a severe
autosomal recessive disorder with early onset and poor prognosis. Mitochondrial
disorders similar to human have been reported in animals. This includes mitochondrial
myopathy in a German Shepherd dog, Alaskan Husky encephalopathy (Leigh
syndrome), and sensory ataxic neuropathy in Golden Retriever dogs.
Diagnosis of human mitochondrial disorders is challenging due to the clinical and
genetic heterogeneity. Even the analysis of the small 16.6 kb mitochondrial genome is
a great challenge. In general, comprehensive analyses involve the application of
multiple different methodologies including Sanger sequencing for the detection of point
mutations, ARMS qPCR for quantification of heteroplasmy, and array comparative
genome hybridization or PCR/sequencing to determine deletion breakpoints. These
procedures are tedious. Recently, the clinical application of next generation deep
sequencing technology resolves these hurdles in one-step.
Mutations in mitochondrial DNA cause a broad spectrum of diseases with the
major clinical features involving muscle and nerve. Tissue distribution and the degree
of mtDNA mutation heteroplasmy determine the clinical phenotype. Mitochondrial
myopathy may be caused by mtDNA point mutations and large deletions, which may be
secondary to nuclear gene defects. The novel next generation sequencing technology
provides a comprehensive clinical molecular diagnostic approach to mtDNA disorders.
Selected reading
1. Smeitink J, van den Heuvel L, DiMauro S. 2001. The genetics and pathology of
oxidative phosphorylation. Nat Rev Genet 2: 342-52
2. Baranowska I et al. 2009. Sensory ataxic neuropathy in golden retriever dogs is
caused by a deletionin the mitochondrial tRNAtyr gene. PLoS Genet 5:e1000499
3. Paciello O, et al. 2003. Mitochondrial myopathy in a German Shepherd dog. Vet
Pathol 40:507-511