BCHS-4361-09-MITOCHO_39180

BCHS-4361-09-MITOCHO_39180 - Diseases associated with the...

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Diseases associated with the mitochondria Krebs cycle defects Fatty acid b oxidation defects Urea cycle defects Electron transport defects Biogenesis errors-errors in translation Errors in mitochondrial inport
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The mitochondrion Note the large surface area of the cristae
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Overview of Mito function There are about 100 or so mitochondria per cell and each mitochondria may have up to 100 genome copies.
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Maternal Inheritance Mitochondria are indispensable and complete loss of function leads to death. However each cell can contain many mitochondria from a few to a 1000 depending on the cell type . Mitochondria have their own DNA. Energy demanding tissue have more mitochondria than non energy demanding tissues. Brain and nerve tissue are very high in mitochondria. Heteroplasy- more than one type of mitochondria in the cell.
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How mitochondrial symptoms increase through a bottleneck
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Diagnostic Testing for Mitochondrial Disease 1.Blood White blood cells or platlets for mtDNA (PCR and Southern) 2.Blood and CSF (spinal fluid) for Lactate and Pyruvate, or Brain MRI Spectroscopy 3.Urine Organic Acids (by GC/MS) 4.Plasma and Urine Amino Acids 5.Blood and Urine Carnitine 6.Brain MRI 7.Muscle Biopsy and Skin Biopsy, Neuropathology and Electron Microscopy, Mitochondrial Electron Transport Studies, Fresh (coupled) mitochondrial Polarography, Muscle mtDNA (PCR and Southern) Taken from Mitochondrial News, Spring 2000 Issue, by Dr. Robert K. Naviaux
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Mito DNA Human mitochondrial DNA is 16 Kbp Each strand is transcribed at one start point. H (heavy) strand and L ) light)strand. H strand- 28 genes, L strand- 9 genes 13 mitochondrial membrane spanning subunits, 2 rRNAs and 22 tRNAs. (a subset of all tRNAs) wobble bases are interchangable. While 83 electron transport subunits are nuclear encoded, over 800 – 1000 total proteins need to be imported. Energetic cost is about 100,000 ATP per 100 amino acids!!
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D-loop (7% of sequence) is a non coding variable part of the genome, where the promoters are and these sequences are used in looking at genetic variation in humans. Mitochondrial mutations are about 6-17 per 100,000 population. Genetic code is different than the universal code. Different codons for tryptophan, stop, arginine and isolucine. Replication lacks proofreading and has a bacterial-like DNA polymerase sensitive to AZT and ddI. Mutation rates are 10 –100 x that of the nuclear DNA.
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Division of transcripts between mitochondria and the nucleus including inhibitors of transcription and translation
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Skewed heteroplasy- one tissue may pass the disease threshold while other tissues may not. Brain, Heart, and Muscle are very susceptible to a diseased state Homoplasmic: Similar distribution of mtDNA mutation in all tissues. Heteroplasmic: Variable distribution of mtDNA mutation in
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BCHS-4361-09-MITOCHO_39180 - Diseases associated with the...

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