Biotechdaily - Human Mitochondrial Mutations Repaired by New Technique - 2 views
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researchers have identified a generic approach to correct mutations in human mitochondrial DNA by targeting corrective RNAs,
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In adults, many aging disorders have been associated with defects of mitochondrial function, including diabetes, Parkinson’s disease, cancer, heart disease, stroke, and Alzheimer’s disease.
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The introduction of nucleus-encoded small RNAs into mitochondria is critical for the replication, transcription, and translation of the mitochondrial genome,
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The study defined a new role for a protein called polynucleotide phosphorylase (PNPASE) in regulating the import of RNA into mitochondria. Reducing the expression--or output--of PNPASE decreased RNA import, which impaired the processing of mitochondrial genome-encoded RNAs. Reduced RNA processing inhibited the translation of proteins required to maintain the mitochondrial electron transport chain that consumes oxygen during cell respiration to produce energy. With reduced PNPASE, unprocessed mitochondrial-encoded RNAs accumulated, protein translation was inhibited, and energy production was compromised, leading to stalled cell growth.
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Geng Wang developed a strategy to target and import specific RNA molecules encoded in the nucleus into the mitochondria and, once there, to express proteins needed to repair mitochondrial gene mutations.
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First, the researchers had to find a way to stabilize the reparative RNA so that it was moved out of the nucleus and then localized to the mitochondrial outer membrane. This was accomplished by modifying an export sequence to direct the RNA to the mitochondrion. Once the RNA was in the area of the transport machinery on the mitochondrial surface, then a second transport sequence was required to direct the RNA into the targeted organelle. With these two modifications, a wide range of RNAs were targeted to and imported into the mitochondria, where they worked to repair defects in mitochondrial respiration and energy production in two different cell line models of human mitochondrial disease.
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