Inherited Mitochondrial DNA Depletion

Abstract

Mitochondria are believed to be direct descendants of a bacterial endosymbiont (most likely Rickettsia prowazekii) that became established~1.5 billion years ago, in a nucleuscontaining host cell. The low gene content of mammalian mtDNA compared with even the smallest known eubacterial genomes appears to imply a relatively rapid and extensive loss or transfer of genetic information from the mitochondria to the nucleus and a compensatory import of nuclear encoded proteins into the mitochondria (1). It is not completely understood why mitochondrial genes moved to the nuclear genome, how they survived their voyage, and whether this process seized to occur. Transfer of genes to the nucleus may have been favored by the genetic principle, which predicts that deleterious, but sub-lethal, mutations accumulate more rapidly in an asexually propagated genome (mtDNA) than in a sexually propagated one (nuclear DNA), ultimately dooming the former to extinction (2). Gene retention in the mitochondria, on the other hand,

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

“…Genetic 'mtDNA depletion syndromes' 48,49 offer support for the reasoning used in generating these experimental models and for the data obtained from them. In those illnesses, mitochondrial and cytoplasmic nucleotide pools are disturbed by mutations of kinases, transporters, and enzymes involved in nucleotide pool homeostasis.…”

Molecular bases of hearing loss in multi-systemic mitochondrial cytopathy

“…Mitochondrial DNA depletion syndromes are caused by defects of mtDNA replication and maintenance of deoxynucleotide pools and are transmitted mainly in an autosomal recessive fashion. 55 In the published literature, deafness has been reported in a phenotype characterized by a late onset and slower progression in four children with multi-systemic involvement and mtDNA depletion. Three of these patients met diagnostic criteria for Kearns-Sayre syndrome which has not been typically associated with mitochondrial DNA depletion.…”

“…56 The median age of onset of hearing loss in our patients with mtDNA depletion was thirteen years. Since the majority of the patients affected with mtDNA depletion syndromes usually have an earlier onset and more severe course, 55 it is possible that many of the patients described in the literature have succumbed prior to any formal hearing evaluation.…”

Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase γ (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study

“…This observation may open new possibilities for further therapy trials and may explain the occasionally observed reversibility of mtDNA depletion [47–49]. The mechanisms, however, underlying the expression of tissue selectivity and the reversibility remain still unclear [50, 51].…”