Controlling the topology of mammalian mitochondrial DNA

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.

The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?

“…Indeed, mtDNA may be more susceptible to damage than nuclear DNA (nDNA) due to its proximity with the free radical-respiratory chain, the lack of protective histones lower fidelity of mitochondrial polymerase γ (POLG), and limited repair mechanisms [ 48 , 54 , 58 , 59 ]. As the mitochondrial producing genome, similar to its bacterial ancestors, has no introns and only one major non-coding region (NCR), any point mutation or deletion could disrupt cellular respiration [ 60 , 61 ]. Oxidative stress is considered as one of the factors negatively influencing mtDNA.…”

Two type I topoisomerases maintain DNA topology in human mitochondria

“…This creates a substantial delay between the initiation of leading- and lagging-strand synthesis from distinct sites on the genome. It is conceivable that this mechanism would generate the ssDNA gaps required for TOP3A to act as the sole decatenase in mitochondria ( 26 , 47 ). Such a model would be consistent with our results indicating that the loss of TOP3A results in the accumulation of hemicatenated replication termination intermediates ( 28 ).…”

“…Type II topoisomerase activities have been described in mitochondrial fractions ( 40–43 ), and later studies have suggested a mitochondrial localisation for either a truncated form of TOP2B ( 44 ), or full-length TOP2B and TOP2A ( 45 , 46 ). The exact roles and contributions of topoisomerases to maintaining mtDNA topology during mtDNA replication and transcription remain poorly understood ( 47 ).…”

Possible frequent multiple mitochondrial DNA copies in a single nucleoid

“…Moreover, mtDNA is organized in the form of nucleo-protein complexes termed nucleoids [18][19][20][21][22][23], which contain yet unde ned number of copies of double-stranded (ds) mtDNA. Biology of nucleoids is still largely unknown.…”

“…They oppose the processes of mitophagy and mtDNA degradation, establishing homeostasis. Other gene expression machinery and mtDNA repair proteins permanently exist within or are recruited to the nucleoid structure [18][19][20]23].…”