Probing the Pathogenicity of Patient-derived Variants of MT-ATP6 in Yeast

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2023 Apr 21

PMID 37083953

Authors

Emilia Baranowska

Katarzyna Niedzwiecka

Chiranjit Panja

Camille Charles

Alain Dautant

Jaroslaw Poznanski

Jean-Paul di Rago

Deborah Tribouillard-Tanvier

Roza Kucharczyk

Affiliations

Soon will be listed here.

Abstract

The list of mitochondrial DNA (mtDNA) variants detected in individuals with neurodegenerative diseases is constantly growing. Evaluating their functional consequences and pathogenicity is not easy, especially when they are found in only a limited number of patients together with wild-type mtDNA (heteroplasmy). Owing to its amenability to mitochondrial genetic transformation and incapacity to stably maintain heteroplasmy, and the strong evolutionary conservation of the proteins encoded in mitochondria, Saccharomyces cerevisiae provides a convenient model to investigate the functional consequences of human mtDNA variants. We herein report the construction and energy-transducing properties of yeast models of eight MT-ATP6 gene variants identified in patients with various disorders: m.8843T>C, m.8950G>A, m.9016A>G, m.9025G>A, m.9029A>G, m.9058A>G, m.9139G>A and m.9160T>C. Significant defect in growth dependent on respiration and deficits in ATP production were observed in yeast models of m.8950G>A, m.9025G>A and m.9029A>G, providing evidence of pathogenicity for these variants. Yeast models of the five other variants showed very mild, if any, effect on mitochondrial function, suggesting that the variants do not have, at least alone, the potential to compromise human health.

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