Download Progress and Challenges in Understanding the Mechanisms of

Pathogenesis of Mitochondrial Disorders
Eric A. Shoubridge
Montreal Neurological Institute and Department of Human Genetics
McGill University, Montreal
The mitochondrial oxidative phosphorylation (OXPHOS) system, responsible for
aerobic energy production in nearly all cells in our body, comprises four enzyme complexes
(Complexes I-IV) that make up the mitochondrial respiratory chain itself, and the ATP synthase
complex (Complex V), which uses the energy generated by electron transport along the
respiratory chain to produce ATP. The subunits of the five enzyme complexes are encoded in
both the nuclear and mitochondrial genomes; of the 82 structural subunits, 13 are encoded in the
mitochondrial genome (mtDNA), which also codes for the two rRNAs and 16 tRNAs necessary
for their translation. OXPHOS deficiencies are an important cause of a wide range of
neurological, neuromuscular, cardiac and endocrine disorders, and even some cancers
(Koopman et al., 2012; Nunnari and Suomalainen, 2012; Schon and Przedborski, 2011;
Ylikallio and Suomalainen, 2012), the minimum prevalence of which is estimated at ~1:5000
(Chinnery, 2001). The molecular basis for this extraordinary range of clinical phenotypes
remains an enduring mystery.
Mutations in mtDNA are the most frequent cause of mitochondrial disease in adults and
more than 100 such pathogenic mutations have been identified. In the pediatric population the
majority of OXPHOS disorders (~80%) are transmitted as autosomal recessive traits, usually
with a severe phenotype and a fatal outcome. More than 100 nuclear genes have now been
associated with OXPHOS disorders, and with the advent of whole exome sequencing that
number is expanding rapidly.
The genetics of mtDNA are completely different than that of nuclear genes. MtDNA is
maternally inherited in mammals and it exists as a thousand copy genome. Nearly all diseasecausing mutations are heteroplasmic, meaning that both wild-type and mutant genomes are
segregating in different cell types. Transmission of mutant mtDNAs from generation to
generation is largely stochastic, but segregation can be rapid due to the presence of a bottleneck
in germline development. This makes genetic counselling of mtDNA mutation carriers
challenging. Interestingly, the majority of human pathogenic mutations occur in tRNA genes, as
there appears to be a filter in development that selects against the most severe mutations in the
structural genes. A biochemical, and therefore clinical, phenotype is not seen until the
proportion of mutant geneomes exceeds a particular threshold. Generally, mutations in
particular mtDNA genes are associated with specific and largely non-overlapping phenotypes.
The molecular basis for this is not well understood.
As mtDNA itself encodes for only a handful of genes the replication, maintenance,
transcription, and translation of the genome is entirely dependent upon nuclear encoded,
mitochondrially targeted proteins. Belying the evolutionary origins of mitochondria from proteobacteria, the enzymes responsible for mtDNA replication and transcription are
homologous to those in bacteriophage. The translation machinery responsible for synthesizing
the 13 mtDNA-encoded polypeptides, however, does resembles that in prokaryotes. Defects
related to the handling and processing of mitochondrial mRNAs and mitochondrial translation
have emerged as a important causes of OXPHOS disease, but the posttranscriptional regulation
of mammalian mitochondrial gene expression is only beginning to be understood.
The molecular pathogenesis of these disorders has been studied in a variety of animal
(Tyynismaa and Suomalainen, 2009) models and in cells cultured from patients with
mitochondrial disease. Despite the Mendelian genetics, disorders due to nuclear gene defects
have even broader phenotyic variability than mtDNA related disorders. Although this is very
incompletely understood, it is clear that a number of factors contribute to this including nuclear
background, cell-type specific organization of the translation apparatus, and the ability of
different cell types to adapt to the genetic defect. I will discuss recent progress in this area,
future directions, and challenges.
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Koopman, W.J., Willems, P.H., and Smeitink, J.A. (2012). Monogenic mitochondrial
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Nunnari, J., and Suomalainen, A. (2012). Mitochondria: in sickness and in health. Cell 148,
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Schon, E.A., and Przedborski, S. (2011). Mitochondria: the next (neurode)generation.
Neuron 70, 1033-1053.
Tyynismaa, H., and Suomalainen, A. (2009). Mouse models of mitochondrial DNA defects
and their relevance for human disease. Embo Rep 10, 137-143.
Ylikallio, E., and Suomalainen, A. (2012). Mechanisms of mitochondrial diseases. Annals of
medicine 44, 41-59.