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A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations
- Source :
- International Journal of Molecular Sciences, Vol 22, Iss 4461, p 4461 (2021), International Journal of Molecular Sciences, Volume 22, Issue 9, International Journal of Molecular Sciences, 2021, 22, ⟨10.3390/ijms22094461⟩, International Journal of Molecular Sciences, MDPI, 2021, 22 (9), pp.4461. ⟨10.3390/ijms22094461⟩, International Journal of Molecular Sciences, MDPI, 2021, 22, ⟨10.3390/ijms22094461⟩, International Journal of Molecular Sciences, 2021, 22 (9), pp.4461. ⟨10.3390/ijms22094461⟩
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations.
- Subjects :
- 0301 basic medicine
[SDV]Life Sciences [q-bio]
medicine.disease_cause
di Punzio
0302 clinical medicine
A
Donnini
C. A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations. Int yeast model
Missense mutation
Sellem
Biology (General)
Spectroscopy
Genetics
Mutation
mitochondrial diseases
M.A
T
General Medicine
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Phenotype
L
3. Good health
Computer Science Applications
Nuclear DNA
Chemistry
Mitochondrial DNA
QH301-705.5
Lodi
Oxidative phosphorylation
Biology
Catalysis
Inorganic Chemistry
03 medical and health sciences
C
G
medicine
Physical and Theoretical Chemistry
ANT1 mutations
Molecular Biology
Gene
QD1-999
Dallabona
[SDV.GEN]Life Sciences [q-bio]/Genetics
Di Noia
Organic Chemistry
Palmieri
yeast model
Yeast
030104 developmental biology
Delahodde
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 22
- Issue :
- 4461
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....c9214408afdb07ac4d68cc65ec64387f