The Role of Apoptosis Inducing Factor In modulating mtDNA copy number

Abstract

Mitochondrial DNA (mtDNA) encodes essential components of the mitochondrial electron transport chain. Depletion and mutations of mtDNA cause mitochondrial dysfunctions resulting in numerous human diseases, including neurodegeneration and mitochondrial disorders. However, despite extensive research, mechanisms that control mtDNA copy number are largely unknown. <br /> The present study demonstrates that Apoptosis Inducing Factor (AIF), a mitochondrial protein with a dual role in cell-death and mitochondrial maintenance, is involved in the regulation of mtDNA. AIF deficiency resulted in a significant, several-fold increase of mtDNA copy number and this effect was evolutionary conserved among species. AIF regulates mtDNA copy number independently of previously described mechanisms controlling mtDNA content, including the activity of key mtDNA replication proteins, mitochondrial fusion, fission and biogenesis. However, inhibition of the cell cycle regulator CYE-1/cyclin E and the DNA damage response kinase ATL-1/ATR abrogated the effect of AIF deficiency on mtDNA copy number.<br /> These findings provide new insights into the physiological functions of AIF and the regulatory pathways controling mtDNA quantity. As AIF as well as mtDNA dysregulation causes severe mitochondrial disorders in humans, this study extends our knowledge of molecular mechanisms underlying these pathologies and thereby may contribute to the development of novel therapeutic targets.