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Updated: Oct 12, 2025
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the
Giulia di Punzio1, Micol Gilberti1, Enrico Baruffini1
1Department of Chemistry Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
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.
Insights
Researchers identified ten drugs that stabilize mitochondrial DNA (mtDNA) by increasing the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool. These findings offer potential new therapies for mitochondrial DNA depletion syndromes (MDS).
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Mitochondrial DNA depletion syndromes (MDS) are severe genetic disorders characterized by reduced mitochondrial DNA (mtDNA) copy number.
- The MPV17 gene, encoding an inner mitochondrial membrane channel, is implicated in hepatocerebral MDS and Navajo neurohepatopathy.
- Yeast models are crucial for studying mitochondrial diseases and discovering novel therapeutic agents.
Purpose of the Study:
- To identify potential therapeutic compounds for MPV17-related disorders using a yeast model.
- To investigate the mechanism by which identified compounds restore mtDNA stability.
- To assess the broader applicability of these compounds to other MDS models.
Main Methods:
- Modeled MPV17 disorder in yeast using the homologous gene, SYM1.
- Conducted high-throughput screening to identify drugs affecting mtDNA stability.
- Quantified mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pools and mtDNA stability.
- Tested identified compounds in additional yeast models of MDS.
Main Results:
- Ten drugs were identified that significantly increase the mtdNTP pool and enhance mtDNA stability in the Sym1 yeast model.
- The results suggest that reduced availability of DNA synthesis precursors contributes to mtDNA depletion in Sym1 deficiency.
- The identified drugs demonstrated efficacy in stabilizing mtDNA in two other MDS yeast models.
Conclusions:
- The study identified ten novel compounds with the potential to treat MPV17-related disorders.
- These compounds act by increasing the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool, thereby stabilizing mitochondrial DNA (mtDNA).
- The findings suggest a broader therapeutic potential for these drugs across various mitochondrial DNA depletion syndromes (MDS).
