The human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16 569 bp and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 polypeptides. Mitochondria genes are outside the nucleus and are more prone to defects and damage. Aubrey de Grey and the SENS research team are looking to move the mitochondria genes into the cell nucleus where they will be more protected. They have successfully moved two of the genes into the nucleus where the genes are producing their proteins.
Mitochondrial damage is one of seven types of age related damage that SENS and others are working to fix towards the goal of radical life extension.
Mitochondria carry out oxidative phosphorylation principally by using pyruvate, fatty acids and amino acids to generate adenosine triphosphate (ATP). In animals, mitochondria are the only cellular organelles that possess their own DNA, mitochondrial DNA (mtDNA), which in humans contains 37 genes including genes encoding mitochondrial tRNAs, mitochondrial rRNAs and 13 oxidative phosphorylation (OxPhos) complex proteins. The rest of the mitochondrial proteins and RNAs are encoded by nuclear DNA and these proteins must be imported into the mitochondria after cytoplasmic translation.
Both pediatric and adult-onset diseases have been identified that are caused by point mutations or partial deletions in mtDNA. Approximately 7.5 out of every 100 000 people are estimated to suffer from a diagnosed mtDNA disease, while 1 in 200 people are estimated to be born with a deleterious mtDNA mutation, suggesting that mitochondrial disease might be underdiagnosed.
Although defects in the oxidative phosphorylation system can cause disease in essentially every organ system in the body, most symptoms occur predominantly in nervous, cardiovascular and skeletal muscle tissues. Leber’s hereditary optic neuropathy (LHON), Leigh syndrome, mitochondrial encephalopathy, chronic progressive external ophthalmoplegia and Kearns–Sayre syndrome are examples of neurological and muscular diseases associated with mtDNA mutations. Other mtDNA diseases include non-hypoxic lactic acidosis and Pearson marrow-pancreas syndrome.
Mitochondrial diseases tend to be fairly complex, with patients often presenting with multiple symptoms, and/or suffering from symptoms that differ between patients with the same mtDNA mutation. Traditional approaches include palliative treatments such as surgery or drugs, but are of limited use for mitochondrial diseases because they fail to address the underlying defect in the mtDNA. In some cases, specific disease symptoms may be ameliorated by surgery, such as cochlear implants for some sensorineural hearing loss patients, cataract surgery for ocular manifestations of mitochondrial disease, or heart transplants for selected mitochondrial cardiomyopathy patients. Other symptoms are sometimes alleviated with pharmacologic therapies that partially address metabolic defects downstream of the mutations, such as by scavenging reactive oxygen species or reducing excessive lactate accumulation
SENS researchers explored the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. They have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 andATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with theATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, they report the stable allotopic expression, import and function of two mitochondria encoded genes,ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.
SOURCES- Nucleic Acids Research, SENS
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