OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA680923 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR13150104.fastq.gz | Fastqsanger.gz | |||
| SRR13150105.fastq.gz | Fastqsanger.gz | |||
| SRR13150106.fastq.gz | Fastqsanger.gz | |||
| SRR13150107.fastq.gz | Fastqsanger.gz | |||
| SRR13150108.fastq.gz | Fastqsanger.gz |
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Project description:Reduction of mitochondrial membrane potential is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain mitochondrial membrane potential, which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA respectively, have graded reduction of mitochondrial membrane potential and proliferation rates. Extensive omics analyses of these mutants show that accompanying mitochondrial membrane potential reduction, these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain mitochondrial membrane potential, ISC biosynthesis, and cell proliferation.
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Project description:Reduction of mitochondrial membrane potential is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain mitochondrial membrane potential, which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA respectively, have graded reduction of mitochondrial membrane potential and proliferation rates. Extensive omics analyses of these mutants show that accompanying mitochondrial membrane potential reduction, these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain mitochondrial membrane potential, ISC biosynthesis, and cell proliferation.
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Project description:Defective complex I (CI) is the most common type of oxidative phosphorylation (OXPHOS) disease in patients, with an incidence of 1 in 5,000 live births. Complex I deficiency can present in infancy or early adulthood and shows a wide variety of clinical manifestations, including Leigh syndrome, (cardio)myopathy, hypotonia, stroke, ataxia and lactic acidosis. A number of critical processes and factors, like superoxide production, calcium homeostasis, mitochondrial membrane potential and mitochondrial morphology, are known to be involved in clinical CI deficiency, but not all factors are yet known and a complete picture is lacking. Therefore, whole genome gene expression profiling was performed in fibroblasts of CI deficient patients and controls, comparing glycolytic and oxidative conditions. Linear regression and pathway analysis identified a number of key adaptive processes. Fibroblasts were derived from skin biopsies of five patients homozygous or compound heterozygous for nuclear complex I mutations and five controls. The groups were matched for age and sex.
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Project description:Defective complex I (CI) is the most common type of oxidative phosphorylation (OXPHOS) disease in patients, with an incidence of 1 in 5,000 live births. Complex I deficiency can present in infancy or early adulthood and shows a wide variety of clinical manifestations, including Leigh syndrome, (cardio)myopathy, hypotonia, stroke, ataxia and lactic acidosis. A number of critical processes and factors, like superoxide production, calcium homeostasis, mitochondrial membrane potential and mitochondrial morphology, are known to be involved in clinical CI deficiency, but not all factors are yet known and a complete picture is lacking. Therefore, whole genome gene expression profiling was performed in fibroblasts of CI deficient patients and controls, comparing glycolytic and oxidative conditions. Linear regression and pathway analysis identified a number of key adaptive processes.
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Project description:CRIF1 is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane. Beta cell specific Crif1 haploinsufficiency resulted in defect of first phase insulin secretion, and caused islet cell composition change as well as proliferation of beta cell for a compensation to maintain metabolic homeostasis. These results suggest that mitochondrial OxPhos function of beta cell has roles for beta cell compensation as well as insulin secretion.
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