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A mitochondrial etiology of metabolic and degenerative diseases, cancer and aging (94.1)
Author(s) -
Wallace Douglas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.94.1
Subject(s) - heteroplasmy , mitochondrial dna , biology , genetics , mutation , phenotype , mutant , mitochondrial myopathy , epigenome , mitochondrial disease , gene , dna methylation , gene expression
Mitochondrial defects have been implicated in a broad spectrum of metabolic and degenerative diseases and can result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, changes in the epigenome, and environmental perturbations. Clinically relevant mtDNA variation can result from ancient polymorphisms, recent deleterious mutations, and somatic mutations. Proof that mtDNA mutations can cause disease has been obtained by introducing mtDNA mutations into the mouse via embryonic stem cells (mESCs). Introduction of a COI (nt T6589C, V421A) mutation resulted in myopathy and cardiomyopathy, an ND6 nt G13997A (P25L) mutation in optic atrophy and a parkinsonian phenotype, and mixing two normal but different mtDNAs resulted in neuropsychiatric dysorder and learning problems. Mixtures of mutant and normal mtDNAs (heteroplasmy) can generate very different phenotypes. The tRNA Leu(UUR) nt 3243A>G mutation is associated with autism or diabetes at 0‐37% 3243G mutant, neuromuscular degenerative disease at 50‐90% mutant, and perinatal lethal diseases at ~100% mutant. Cell cybrids harboring different percentages of the 3243G mutant have revealed that the different phenotypes correspond with marked changes in the nDNA gene expression profile and hence in the epigenome and signal transduction systems.