Mitochondrial DNA PDF 2025

WE MAKE DOCTORS Mitochondrial DNA Ana Gabriela Colima Fausto, PhD Learning objectives Describe the characteristics of mitochondrial DNA Explain the mitochondrial DNA replication process Contrast the peculiarities of the genetic code in mitochondrial DNA Identify the mechanisms of dam...

WE MAKE DOCTORS Mitochondrial DNA Ana Gabriela Colima Fausto, PhD Learning objectives Describe the characteristics of mitochondrial DNA Explain the mitochondrial DNA replication process Contrast the peculiarities of the genetic code in mitochondrial DNA Identify the mechanisms of damage to mitochondrial DNA Highlight the main characteristics of mitochondrial diseases Mention the most common mitochondrial diseases Compare the concepts of homoplasmy and heteroplasmy Mitochondria Discovered in 1963, by Margit Nass and Sylvan Nass Mitochondria: support energy to the cell Signaling, cellular differentiation, and cell death, as well as maintaining control of the cell cycle and cell growth Hundreds to thousands in the cell Mitochondrial DNA Double stranded, circular molecule. 16,569 base pair 37 genes: 22 tRNA, 2 rRNA, 13 proteins for oxidative phosphorylation (respiratory complexes I, III, IV and V) 2 chains: heavy (28) and light (9) 2 to 10 copies of its DNA Mitochondrial DNA D-loop is involved in the regulation of transcription and replication of the molecule, and is the only region not directly involved in the synthesis of respiratory chain polypeptides. MT-ND1 through MT-ND6 and MT- ND4L encode seven subunits of complex I. Cyt b is the only mtDNA-encoded complex III subunit. MT-CO1 to MT-CO3 encode for three of the complex IV (cytochrome c oxidase, or COX) subunits. MT-ATP6 and MT-ATP8 encode for two subunits of complex V: ATPase6 and ATPase8, respectively. OH and OL are the origins of heavy- and light- strand mtDNA replication.  Mitochondrial DNA Policistronic Not packaged into chromatin No introns, no 5´cap Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome Few, if any, noncoding DNA sequences. Three percent of the mitochondrial genome is noncoding DNA, whereas 93% of the nuclear genome is noncoding DNA. Mitochondrial DNA Constant replication, regardless of the cycle and the cell type Asynchronous replication: different times and with two different origins (OH-OL) in opposite directions Bidirectional replication Mitochondrial DNA Genetic code is not universal for mDNA UGA codon: tryptophan AUG and AUA codons: Methionine UAA, UAG, AGA and AGG: Stop codons Mitochondrial DNA damage Expose to oxidative damage by free radicals Not protected by histones DNA repair mechanisms not as efficient as in nDNA Mutation rate 10 times higher than nDNA Mitochondrial diseases: mitochondrial DNA and nuclear DNA Mitochondrial diseases Disorders that arise as a result of dysfunction of the mitochondrial respiratory chain Single or multiple organs involved: neurologic and myopathic features Mitochondrial disorders may present at any age: mDNA (childhood), nDNA (adults) Clinical variability  Prevalence of 1:8500 Common clinical features: ophthalmoplegia, myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Chorea and dementia may also be prominent features Mitochondrial diseases Leigh syndrome LHON = Leber hereditary optic neuropathy MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes MERRF = myoclonic epilepsy with ragged-red fibers MIRAS = mitochondrial recessive ataxia syndrome NARP = neurogenic weakness with ataxia and retinitis pigmentosa SANDO = sensory ataxia neuropathy, dysarthria, ophthalmoplegia SCAE = spinocerebellar ataxia with epilepsy CPEO = chronic progressive external ophthalmoplegia KSS = Kearns-Sayre syndrome Mitochondrial diseases Uses of mitochondrial DNA Evolution studies Maternal lineage and little recombination Variation in the mitochondrial genome (as well as in the Y chromosome in the case of paternallineages) has been used to delineate how and when humans migrated and occupied the world.