Abstract
The genome of mitochondria, called mtDNA, is a small circular DNA molecule present at thousands of copies per human cell. MtDNA is packaged into nucleoprotein complexes called nucleoids, and the density of mtDNA packaging affects mitochondrial gene expression. Genetic processes such as transcription, DNA replication and DNA packaging alter DNA topology, and these topological problems are solved by a family of enzymes called topoisomerases. Within mitochondria, topoisomerases are involved firstly in the regulation of mtDNA supercoiling and secondly in disentangling interlinked mtDNA molecules following mtDNA replication. The loss of mitochondrial topoisomerase activity leads to defects in mitochondrial function, and variants in the dual-localized type IA topoisomerase TOP3A have also been reported to cause human mitochondrial disease. We review the current knowledge on processes that alter mtDNA topology, how mtDNA topology is modulated by the action of topoisomerases, and the consequences of altered mtDNA topology for mitochondrial function and human health.
Highlights
The mitochondria of eukaryotic cells are the product of an ancient endosymbiotic merger between an alpha-proteobacterium and a host cell [1]
We explore the factors that impact upon mtDNA topology, the mechanisms that regulate this topology and the consequences when these mechanisms are dysfunctional
These results suggest that the control of mtDNA topology by TOP1MT is normally required to regulate mtDNA transcription initiation and possibly termination
Summary
The mitochondria of eukaryotic cells are the product of an ancient endosymbiotic merger between an alpha-proteobacterium and a host cell [1]. A human cell contains between several hundred and several thousand copies of mtDNA, dispersed within the cellular mitochondrial network [4]. Aside from the 13 mtDNA-encoded genes of the OXPHOS complexes, all mitochondrially localized proteins are encoded in the nucleus and must be targeted to mitochondria and post-translationally imported via a specialized import machinery [8]. The mitochondrial genome is under nuclear genetic control, with an estimated 250–300 nuclear-encoded proteins being required for mtDNA expression [9]. Repair or transcribe mtDNA, interacting proteins must manipulate the structure of the DNA molecule in order to gain access to the genetic sequence. The packaging of mtDNA by proteins alters the topology of mtDNA, and the accessibility of sequence elements required for transcription and replication [10]. We explore the factors that impact upon mtDNA topology, the mechanisms that regulate this topology and the consequences when these mechanisms are dysfunctional
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