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1.
Open Biol ; 11(4): 200369, 2021 04.
Article in English | MEDLINE | ID: mdl-33823662

ABSTRACT

Mitochondria are essential for regulation of cellular respiration, energy production, small molecule metabolism, anti-oxidation and cell ageing, among other things. While the mitochondrial genome contains a small number of protein-coding genes, the great majority of mitochondrial proteins are encoded by chromosomal genes. In the fission yeast Schizosaccharomyces pombe, 770 proteins encoded by chromosomal genes are located in mitochondria. Of these, 195 proteins, many of which are implicated in translation and transport, are absolutely essential for viability. We isolated and characterized eight temperature-sensitive (ts) strains with mutations in essential mitochondrial proteins. Interestingly, they are also sensitive to limited nutrition (glucose and/or nitrogen), producing low-glucose-sensitive and 'super-housekeeping' phenotypes. They fail to produce colonies under low-glucose conditions at the permissive temperature or lose cell viability under nitrogen starvation at the restrictive temperature. The majority of these ts mitochondrial mutations may cause defects of gene expression in the mitochondrial genome. mrp4 and mrp17 are defective in mitochondrial ribosomal proteins. ppr3 is defective in rRNA expression, and trz2 and vrs2 are defective in tRNA maturation. This study promises potentially large dividends because mitochondrial quiescent functions are vital for human brain and muscle, and also for longevity.


Subject(s)
Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mutation , Phenotype , Schizosaccharomyces pombe Proteins/genetics , Schizosaccharomyces pombe Proteins/metabolism , Schizosaccharomyces/physiology , Energy Metabolism , Gene Expression Profiling , Gene Expression Regulation, Fungal , Genes, Essential , Humans , Stress, Physiological
2.
Sci Adv ; 4(8): eaat5685, 2018 08.
Article in English | MEDLINE | ID: mdl-30116786

ABSTRACT

Quiescent (G0 phase) cells must maintain mitotic competence (MC) to restart the cell cycle. This is essential for reproduction in unicellular organisms and also for development and cell replacement in higher organisms. Recently, suppression of MC has gained attention as a possible therapeutic strategy for cancer. Using a Schizosaccharomyces pombe deletion-mutant library, we identified 85 genes required to maintain MC during the G0 phase induced by nitrogen deprivation. G0 cells must recycle proteins and RNA, governed by anabolism, catabolism, transport, and availability of small molecules such as antioxidants. Protein phosphatases are also essential to maintain MC. In particular, Nem1-Spo7 protects the nucleus from autophagy by regulating Ned1, a lipin. These genes, designated GZE (G-Zero Essential) genes, reveal the landscape of genetic regulation of MC.


Subject(s)
Autophagy , Cell Nucleus/genetics , Gene Expression Regulation, Fungal , Mitosis , Resting Phase, Cell Cycle/physiology , Schizosaccharomyces pombe Proteins/genetics , Schizosaccharomyces/genetics , Cells, Cultured , Metabolome , Schizosaccharomyces/growth & development , Schizosaccharomyces/metabolism , Schizosaccharomyces pombe Proteins/metabolism
3.
Open Biol ; 8(3)2018 03.
Article in English | MEDLINE | ID: mdl-29593117

ABSTRACT

Rapamycin inhibits TOR (target of rapamycin) kinase, and is being used clinically to treat various diseases ranging from cancers to fibrodysplasia ossificans progressiva. To understand rapamycin mechanisms of action more comprehensively, 1014 temperature-sensitive (ts) fission yeast (Schizosaccharomyces pombe) mutants were screened in order to isolate strains in which the ts phenotype was rescued by rapamycin. Rapamycin-rescued 45 strains, among which 12 genes responsible for temperature sensitivity were identified. These genes are involved in stress-activated protein kinase (SAPK) signalling, chromatin regulation, vesicle transport, and CoA- and mevalonate-related lipid metabolism. Subsequent metabolome analyses revealed that rapamycin upregulated stress-responsive metabolites, while it downregulated purine biosynthesis intermediates and nucleotide derivatives. Rapamycin alleviated abnormalities in cell growth and cell division caused by sty1 mutants (Δsty1) of SAPK. Notably, in Δsty1, rapamycin reduced greater than 75% of overproduced metabolites (greater than 2× WT), like purine biosynthesis intermediates and nucleotide derivatives, to WT levels. This suggests that these compounds may be the points at which the SAPK/TOR balance regulates continuous cell proliferation. Rapamycin might be therapeutically useful for specific defects of these gene functions.


Subject(s)
Lipid Metabolism/drug effects , Mitogen-Activated Protein Kinases/genetics , Mutation , Schizosaccharomyces/growth & development , Sirolimus/pharmacology , Biological Transport/drug effects , Chromatin/metabolism , Coenzyme A/biosynthesis , Fungal Proteins/genetics , Gene Expression Regulation, Fungal/drug effects , Metabolome , Mevalonic Acid/metabolism , Schizosaccharomyces/genetics , Signal Transduction , Temperature
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