Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator

Cristina Dallabona, Renè Massimiliano Marsano, Paola Arzuffi, Daniele Ghezzi, Patrizia Mancini, Massimo Zeviani, Iliana Ferrero, Claudia Donnini

Research output: Contribution to journalArticle

Abstract

A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.

Original languageEnglish
Article numberddp581
Pages (from-to)1098-1107
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number6
DOIs
Publication statusPublished - Mar 2010

Fingerprint

Mitochondrial DNA
Energy Metabolism
Yeasts
Mitochondrial Membranes
Glycogen
Nonoxynol
Genes
Suppressor Genes
Citric Acid Cycle
Organelles
Cytosol
Saccharomyces cerevisiae
Ethanol
Maintenance
Phenotype
Mutation
Temperature
human MPV17 protein
Growth
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Dallabona, C., Marsano, R. M., Arzuffi, P., Ghezzi, D., Mancini, P., Zeviani, M., ... Donnini, C. (2010). Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator. Human Molecular Genetics, 19(6), 1098-1107. [ddp581]. https://doi.org/10.1093/hmg/ddp581

Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator. / Dallabona, Cristina; Marsano, Renè Massimiliano; Arzuffi, Paola; Ghezzi, Daniele; Mancini, Patrizia; Zeviani, Massimo; Ferrero, Iliana; Donnini, Claudia.

In: Human Molecular Genetics, Vol. 19, No. 6, ddp581, 03.2010, p. 1098-1107.

Research output: Contribution to journalArticle

Dallabona, C, Marsano, RM, Arzuffi, P, Ghezzi, D, Mancini, P, Zeviani, M, Ferrero, I & Donnini, C 2010, 'Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator', Human Molecular Genetics, vol. 19, no. 6, ddp581, pp. 1098-1107. https://doi.org/10.1093/hmg/ddp581
Dallabona, Cristina ; Marsano, Renè Massimiliano ; Arzuffi, Paola ; Ghezzi, Daniele ; Mancini, Patrizia ; Zeviani, Massimo ; Ferrero, Iliana ; Donnini, Claudia. / Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 6. pp. 1098-1107.
@article{8e3906052ed945c68cba8a9c5c65cdea,
title = "Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator",
abstract = "A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.",
author = "Cristina Dallabona and Marsano, {Ren{\`e} Massimiliano} and Paola Arzuffi and Daniele Ghezzi and Patrizia Mancini and Massimo Zeviani and Iliana Ferrero and Claudia Donnini",
year = "2010",
month = "3",
doi = "10.1093/hmg/ddp581",
language = "English",
volume = "19",
pages = "1098--1107",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator

AU - Dallabona, Cristina

AU - Marsano, Renè Massimiliano

AU - Arzuffi, Paola

AU - Ghezzi, Daniele

AU - Mancini, Patrizia

AU - Zeviani, Massimo

AU - Ferrero, Iliana

AU - Donnini, Claudia

PY - 2010/3

Y1 - 2010/3

N2 - A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.

AB - A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.

UR - http://www.scopus.com/inward/record.url?scp=77950660127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950660127&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp581

DO - 10.1093/hmg/ddp581

M3 - Article

C2 - 20042463

AN - SCOPUS:77950660127

VL - 19

SP - 1098

EP - 1107

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 6

M1 - ddp581

ER -