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Mar 19, 2012
Three parent offspring and targeted RNA offer promise for treating mitochondrial dysfunction
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MitochondriaOur cells need energy. The majority of this energy comes from adenosine triphosphate (ATP), which is generated by mitochondria. In addition to acting as the powerhouse of the cell through the production of ATP, mitochondria are involved in other processes including cell differentiation, signaling, and cell death. Because mitochondria play such a vital role in cellular energy, defects in mitochondrial function have been linked to a range of diseases including neuromuscular diseases, blindness, deafness, and organ diseases. Additionally, mitochondria dysfunction is linked to aging diseases including Alzheimer’s. Currently, no effective treatment options for abnormal mitochondrial DNA exist, but researchers are exploring several promising paths. 

Mitochondrial diseases arise due to mutations in mitochondrial DNA, which codes for about 37 human genes. Unlike nuclear DNA, which includes two copies of DNA (maternal and paternal), mitochondrial DNA only comes from the mother. This means that diseases arising from abnormal mitochondrial DNA are maternally inherited. Genetic counseling offers prevention for passing on mitochondrial DNA diseases but only for women with minimal abnormal mitochondrial DNA in their oocytes. A new in vitro fertilization (IVF) procedure pioneered by Doug Turnbull of Newcastle University appears promising for situations for women at risk for passing on defective mitochondrial DNA. In this technique, DNA from the mother’s egg is removed and placed into a donor egg. Studies show that these eggs can generate human embryos with minimal transfer of genetic materiel from the donor egg. This means that children born would technically come from ‘three parents,' but should not express donor characteristics.

MitochondrionWhile scientifically and medically promising for the prevention of passing on mitochondrial diseases, ethical and legal considerations arise. IVF already faces a variety of ethical firestorms including the potential for mix-ups, the unregulated nature of procedures resulting in situations like the octomom, and the ability to select for or against traits. This new IVF approach adds another element to the already contentious debate about the ethics of IVF. If the ethical debate was not enough, the laws regarding this technique remain unresolved. Currently, the government in Britain is exploring legal changes to accommodate and regulate these new types of procedures.

If three parent children seem to extreme of an approach, other promising research focuses on restoring mitochondrial function. A research team at the University of California, Los Angeles headed by Drs. Michael Teitell and Carla Koehler has focused on targeted corrective RNA for treating mitochondrial DNA diseases. In 2010, this team showed that polynucleotide phosphorylase (PNPASE) regulates the importation of RNA into the mitochondria. This discovery led to the hypothesis that mitochondrial function could be restored through the importation of targeted RNAs. To do this, RNAs were engineered with an export sequence that direct RNAs from the nucleus to the mitochondria. Once at the mitochondria, a second transport sequence shuttles the RNAs into the mitochondria. This approach was shown to successfully import a variety of RNAs and restore deficits in mitochondrial respiration and energy production, which means that this could be a general approach to fixing a variety of mitochondrial diseases.

Mitochondrial DNA dysfunction is implicated in a variety of untreatable diseases. This means that correcting deficits caused by mitochondrial DNA mutations could improve numerous lives. Approaches in preventing the passing on of abnormal mitochondrial DNA or restoring mitochondrial function appear promising.

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