A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool.

Giulia Di Punzio,Micol Gilberti,Cristina Dallabona,Enrico Baruffini,Claudia Donnini,Tiziana Lodi

doi:10.3390/ijms222212223

Giulia Di Punzio, Micol Gilberti + Show 4 more

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https://doi.org/10.3390/ijms222212223

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Abstract

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.

Highlights

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases
Mitochondrial DNA depletion syndromes (MDS) are often caused by defective proteins involved in the mitochondrial DNA (mtDNA) replication machinery, such as POLG, or in dNTP metabolism, such as p53R2 [1]
The leading hypothesis is that MPV17 deficiency might affect mitochondrial dNTP metabolism, leading to an insufficient availability of dNTPs and consequent mitochondrial DNA depletion

Summary

Introduction

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases. These syndromes are characterized by a reduction, in one or several tissues, of the mitochondrial DNA (mtDNA) copy number. The decrease of this biomarker of mitochondrial function can be caused by mutations in mitochondrial or nuclear genes [1,2]. The reduction of dGTP and dTTP nucleotide pools, observed in mitochondria of rat tissues and fibroblasts derived from patients with mutations in the MPV17 gene, suggest that mitochondrial dNTP insufficiency is the principal cause of mtDNA depletion [12]. The ortholog gene tra/mpv has been related to nucleotide metabolism in zebrafish [13,14], whereas in S. cerevisiae, the ortholog SYM1 has been related to the homeostatic control of tricarboxylic acid cycle (TCA) intermediates [7]

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