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 language | English |
|---|---|
| Article number | ddp581 |
| Pages (from-to) | 1098-1107 |
| Number of pages | 10 |
| Journal | Human Molecular Genetics |
| Volume | 19 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 2010 |
Fingerprint
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
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 journal › Article
}
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 -