Main Ideas!- Disorders of energy metabolism!- Nuclear or mitochrondrial DNA mutations!- Inherited from the mom if mutaiton is in the mitochondrial genome!- Individual has normal + abnormal mitchondria= heteroplasmy - Requires a specific % of abnormal mitochondria in cell/tissue to see disease= threshold effect!- Influenced by tissue specific energy need and degree of heteroplasmy that changes as the cell divides= mitotic segregation Objectives!- To understand the structure and function of the mitochondrion and its DNA!- To understand that mitochrondria function because of proteins encoded in two sets of DNA molecules: nuclear and mitochondrial!- To recognize maternal inheritance - To undersand how inheritance of mitochondria DNA mutations can result in cellular dysfunction!- Compare and contrast the inheritance of mitochrondrial genome to that of the nuclear genome.!!1) To understand the structure and function of the mitochondrion and its DNA - they are abundant cellular organelles--about 1000/cell!- have an external lipid bilayer (permeable out membrane, restrictive inner membrane)!- chief function= respiration (generating E, detoxifying O2 to H2O)!- Beta oxidation, Citric acid cycle, fat and sugar intermediates!- formed via complementation of 2 genetic systems: own DNA + nuclear DNA 2) To understand that mitochrondria function because of proteins encoded in two sets of DNA molecules: nuclear and mitochondrial - Mitochondrial DNA!- about 1% of cellular DNA, 2-10 copies/mitoch., is circular dsDNA!- genes for: 13 polypeptides (for respiratory chain components), 2rRNAs, and 22tRNAs!- don't contain introns!- Nuclear genes encode most (95%) of mitochon. proteins--if proteins are destined for import to mito., they usually have leader peptides 3) To recognize maternal inheritance - All the mitochrondria in all cells come from the mother's egg = maternal inheritance!- High copy #: 100s-1000s/cell!- Heteroplasmy, replicative segregation, and threshold effect determined pheno in mitochondtrial conditions!- Heteroplasmy!= mitochondria contain DNA molecules w/differing seqs!- if more than 1 genetically diff. Mt DNAs are present, the pheno (of the mito, cell, tissue) depends on the distribution of the mutant DNAs - Replicative Segregation!= during cell division (mitosis or meiosis) Mt DNA is distributed randomly into daughter cells!- if cell is heteroplasmic, Mt genotypes of daughter cells can shift!- can drift to mutant, WT, or stay mixed Replicative Segregation- Threshold effect!= new pheno will depend on the threshold req. for expression of a new trait!- gradual change in geno may suddently change pheno when enough MtDNA in a cell are mutant/ineffective 4) To undersand how inheritance of mitochondria DNA mutations can result in cellular dysfunction - Defects of mt DNA genes!- pt mutations and duplications= usually inherit!- mild missense muts: matern. inher. (MI) and nearly homoplasmsic!- deleterious pt muts: MI and generally heteroplasmic!- deletions usually spontaneous and often heteroplasmic!- defined by: molecular nature of defect, severity of enzyme deficity, presence/absence of heteroplasmy - Defect in nuclear-encoded mitochondrial genes - transcription or translation, posttranslational processing!- inherited Mendelianally - Defects in nuclear/mitochondrial communication - mitochondrial DNA depletion syndromes: mendelian in inheritance - these are NOT maternal!!- caused by multiple nuclear genes!- can see deletions/depletion of Mt DNA on tissue biopsy!- genes involved in: mtDNA replication, regulation of Mt dNTP pools needed for mtDNA replication! 5) Compare and contrast the inheritance of mitochrondrial genome to that of the nuclear genome. - Maternal inheritance!= inheritance only through the mom!- following generations are affected, more per gen. than Medelian AD (autosomal dom) or XL (x-linked)!- children of both sexes affected, but no male-to-male transmission!- Wide variation in expression due to: mitotic segregation, threshold effect, complementation in Mt and in a given cell!- Mitochondrial diseases - defined by pheno!- often demonstrate Mt myopathy!- skeletal and cardiac msucle, ragged red fibers, abnormally sized/shaped Mt, paracrystalline arrays!- often see encephalopathy!- affect tissues with high E req.!- can have either Mendelian or maternal inher., depends on
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