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Article

Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase

1
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 211166, China
2
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 00090 Warsaw, Poland
3
Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, CNRS, UMR 5095, F-33000 Bordeaux, France
4
Institut national de la santé et de la recherche médicale, 75000 Paris, France
*
Authors to whom correspondence should be addressed.
These authors contributed to this work equally.
Life 2020, 10(9), 215; https://doi.org/10.3390/life10090215
Received: 31 July 2020 / Revised: 9 September 2020 / Accepted: 17 September 2020 / Published: 22 September 2020
(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)
With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20–30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health. View Full-Text
Keywords: MT-ATP6; m.8909T> C; ATP synthase; nephropathy; oxidative phosphorylation; mitochondrial disease MT-ATP6; m.8909T>; C; ATP synthase; nephropathy; oxidative phosphorylation; mitochondrial disease
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MDPI and ACS Style

Ding, Q.; Kucharczyk, R.; Zhao, W.; Dautant, A.; Xu, S.; Niedzwiecka, K.; Su, X.; Giraud, M.-F.; Gombeau, K.; Zhang, M.; Xie, H.; Zeng, C.; Bouhier, M.; di Rago, J.-P.; Liu, Z.; Tribouillard-Tanvier, D.; Chen, H. Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase. Life 2020, 10, 215. https://doi.org/10.3390/life10090215

AMA Style

Ding Q, Kucharczyk R, Zhao W, Dautant A, Xu S, Niedzwiecka K, Su X, Giraud M-F, Gombeau K, Zhang M, Xie H, Zeng C, Bouhier M, di Rago J-P, Liu Z, Tribouillard-Tanvier D, Chen H. Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase. Life. 2020; 10(9):215. https://doi.org/10.3390/life10090215

Chicago/Turabian Style

Ding, Qiuju, Róża Kucharczyk, Weiwei Zhao, Alain Dautant, Shutian Xu, Katarzyna Niedzwiecka, Xin Su, Marie-France Giraud, Kewin Gombeau, Mingchao Zhang, Honglang Xie, Caihong Zeng, Marine Bouhier, Jean-Paul di Rago, Zhihong Liu, Déborah Tribouillard-Tanvier, and Huimei Chen. 2020. "Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase" Life 10, no. 9: 215. https://doi.org/10.3390/life10090215

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