Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224503 | GEO | 2023/08/17
REPOSITORIES: GEO
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Project description:Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 forms a complex with RCC1L, which together perform NDPK activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
2023-08-17 | GSE224817 | GEO
Project description:Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 forms a complex with RCC1L, which together perform NDPK activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
2023-08-17 | GSE224818 | GEO
Project description:Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 forms a complex with RCC1L, which together perform NDPK activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
2023-08-17 | GSE240576 | GEO
Project description:Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 forms a complex with RCC1L, which together perform NDPK activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
2023-08-23 | PXD044812 | Pride
Project description:Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
2024-06-11 | GSE269535 | GEO
Project description:Background: Transcription control of mitochondrial metabolism is essential for cellular function. A better understanding of this process will aid the elucidation of mitochondrial disorders, in particular of the many genetically unsolved cases of oxidative phosphorylation (OXPHOS) deficiency. Yet, to date only few studies have investigated nuclear gene regulation in the context of OXPHOS deficiency. In this study, we combined RNA sequencing of human complex I-deficient patient cells across 32 conditions of perturbed mitochondrial metabolism, with a comprehensive analysis of gene expression patterns, co-expression calculations and transcription factor binding sites. Results: Our analysis shows that OXPHOS genes have a significantly higher co-expression with each other than with other genes, including mitochondrial genes. We found no evidence for complex-specific mRNA expression regulation in the tested cell types and conditions: subunits of different OXPHOS complexes are similarly (co-)expressed and regulated by a common set of transcription factors. However, we did observe significant differences between the expression of OXPHOS complex subunits compared to assembly factors, suggesting divergent transcription programs. Furthermore, complex I co-expression calculations identified 684 genes with a likely role in OXPHOS biogenesis and function. Analysis of evolutionarily conserved transcription factor binding sites in the promoters of these genes revealed almost all known OXPHOS regulators (including GABP, NRF1/2, SP1, YY1, E-box factors) and a set of six yet uncharacterized candidate transcription factors (ELK1, KLF7, SP4, EHF, ZNF143, and EL2). Conclusions: OXPHOS genes share an expression program distinct from other mitochondrial genes, indicative of targeted regulation of this mitochondrial sub-process. Within the subset of OXPHOS genes we established a difference in expression between subunits and assembly factors. Most transcription regulators of genes that co-express with complex I are well-established factors for OXPHOS biogenesis. For the remaining six factors we here suggest for the first time a link with transcription regulation in OXPHOS deficiency. RNA-SEQ of whole cell RNA in 2 control and 2 complex I deficient patient fibroblast cell lines treated with 4 compounds in duplicate, resulting in a total of 2x2x4x2=32 samples
2015-08-31 | E-GEOD-65634 | biostudies-arrayexpress
Project description:Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we generated a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we generated a COA3Y72C mouse, affected in an assembly factor in early COX1 biogenesis, which displayed a similar yet milder inflammatory phenotype. Our study provides mechanistic insight into how defective mitochondrial gene expression causes tissue-specific inflammation.
2024-07-19 | MTBLS9823 | MetaboLights
Project description:Oxidative phosphorylation (OXPHOS) is essential for the synthesis of the vast majority of ATP in eukaryotic cells. It is carried out by multi-protein assemblies that form the electron transport chain (ETC), which are coupled to the mitochondrial ATP synthase, which uses the proton gradient generated by the ETC to drive ATP synthesis. The assembly of the OXPHOS protein machinery requires the coordinated integration of proteins encoded in the nuclear and the mitochondrial genomes, imposing an additional layer of complexity. While the biogenesis of the individual OXPHOS complexes is well understood, it remains unknown how the assembly of the ETC and ATP synthase is coordinated to achieve the correct stoichiometry of the OXPHOS machinery. Here, we identify the mitochondrial regulatory hub for respiratory assembly (MiRA), which serves as a platform on which complex IV and complex V biogenesis are synchronised to ensure balanced assembly of the ETC and complex V. At the molecular level, this is achieved by a stop-and-go safeguarding mechanism: The novel mitochondrial protein Mra1 binds to and slows down complex IV assembly. Two Go signals are then required for assembly to proceed: Binding of the complex IV assembly factor Rcf2 and interaction with the mitoribosome, which translates the complex V subunit Atp9. Both Go signals induce the clipping and subsequent degradation of Mra1, relieving the molecular brake and allowing parallel maturation of complexes IV and V. The absence of the stop-and-go safety mechanism results in the formation of immature complexes, decreased ATP levels and reduced cell viability. The antagonistic activities at MiRA provide a regulated orchestration of complex IV and V assembly which is essential to avoid the predominance of either complex and an unbalanced ratio of OXPHOS complexes, thus ensuring the correct stoichiometry of protein machineries encoded by two different genomes.
2024-02-16 | PXD044749 | Pride
Project description:Oxidative phosphorylation (OXPHOS) is essential for the synthesis of the vast majority of ATP in eukaryotic cells. It is carried out by multi-protein assemblies that form the electron transport chain (ETC), which are coupled to the mitochondrial ATP synthase, which uses the proton gradient generated by the ETC to drive ATP synthesis. The assembly of the OXPHOS protein machinery requires the coordinated integration of proteins encoded in the nuclear and the mitochondrial genomes, imposing an additional layer of complexity. While the biogenesis of the individual OXPHOS complexes is well understood, it remains unknown how the assembly of the ETC and ATP synthase is coordinated to achieve the correct stoichiometry of the OXPHOS machinery. Here, we identify the mitochondrial regulatory hub for respiratory assembly (MiRA), which serves as a platform on which complex IV and complex V biogenesis are synchronised to ensure balanced assembly of the ETC and complex V. At the molecular level, this is achieved by a stop-and-go safeguarding mechanism: The novel mitochondrial protein Mra1 binds to and slows down complex IV assembly. Two Go signals are then required for assembly to proceed: Binding of the complex IV assembly factor Rcf2 and interaction with the mitoribosome, which translates the complex V subunit Atp9. Both Go signals induce the clipping and subsequent degradation of Mra1, relieving the molecular break and allowing parallel maturation of complexes IV and V. The absence of the stop-and-go safety mechanism results in the formation of immature complexes, decreased ATP levels and reduced cell viability. The antagonistic activities at MiRA provide a regulated orchestration of complex IV and V assembly which is essential to avoid the predominance of either complex and an unbalanced ratio of OXPHOS complexes, thus ensuring the correct stoichiometry of protein machineries encoded by two different genomes.
2024-02-16 | PXD044800 | Pride
Project description:Oxidative phosphorylation (OXPHOS) is essential for the synthesis of the vast majority of ATP in eukaryotic cells. It is carried out by multi-protein assemblies that form the electron transport chain (ETC), which are coupled to the mitochondrial ATP synthase, which uses the proton gradient generated by the ETC to drive ATP synthesis. The assembly of the OXPHOS protein machinery requires the coordinated integration of proteins encoded in the nuclear and the mitochondrial genomes, imposing an additional layer of complexity. While the biogenesis of the individual OXPHOS complexes is well understood, it remains unknown how the assembly of the ETC and ATP synthase is coordinated to achieve the correct stoichiometry of the OXPHOS machinery. Here, we identify the mitochondrial regulatory hub for respiratory assembly (MiRA), which serves as a platform on which complex IV and complex V biogenesis are synchronised to ensure balanced assembly of the ETC and complex V. At the molecular level, this is achieved by a stop-and-go safeguarding mechanism: The novel mitochondrial protein Mra1 binds to and slows down complex IV assembly. Two Go signals are then required for assembly to proceed: Binding of the complex IV assembly factor Rcf2 and interaction with the mitoribosome, which translates the complex V subunit Atp9. Both Go signals induce the clipping and subsequent degradation of Mra1, relieving the molecular brake and allowing parallel maturation of complexes IV and V. The absence of the stop-and-go safety mechanism results in the formation of immature complexes, decreased ATP levels and reduced cell viability. The antagonistic activities at MiRA provide a regulated orchestration of complex IV and V assembly which is essential to avoid the predominance of either complex and an unbalanced ratio of OXPHOS complexes, thus ensuring the correct stoichiometry of protein machineries encoded by two different genomes.
2024-02-16 | PXD044615 | Pride