Regulation of mtDNA Copy Number by the ATM/ATR Signaling Pathway

Abstract

Mitochondrial DNA (mtDNA) encodes essential protein components of the mitochondrial oxidative phosphorylation complexes and is maintained in cells in multiple copies (usually 100–10,000 copies/cell). However, mtDNA copy number is strictly regulated in a tissue-specific manner by largely unknown mechanisms. We recently discovered that Mec1/Rad53 nuclear checkpoint pathway controls mtDNA copy number in yeast. The key target of this pathway is the enzyme ribonucleotide reductase (RNR), which catalyzes the rate-limiting step in de novo deoxynucleoside triphosphate (dNTP) synthesis. The homologous pathway in humans is the ATM/ATR DNA damage checkpoint pathway, which activates RNR via an inducible small subunit of the enzyme called p53R2. Our recent results demonstrate that this pathway is also involved in regulating mtDNA copy in mammalian cells, by acting as novel de novo pathway for the synthesis of dNTPs for replication and maintenance of mtDNA outside of S-phase and during DNA damage. Human mtDNA depletion syndromes are a class of diseases that result from an inability to maintain proper mtDNA levels in tissues, a subset of which result from disruptions in cellular dNTP metabolism. Altogther, our results suggest that disruptions of the ATM/ATR pathway may well be the cause of other mtDNA depletion syndromes and that aberrant mtDNA copy number regulation may underlie the complex pathology of Ataxia-Telangiectasia, a neurodegenerative disease caused by loss-of-function mutations in the ATM (Ataxia-Telangiectasia Mutated) protein kinase.