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Defective mitochondrial translation due to loss of COX14 function triggers ROS-induced inflammation in liver

ABSTRACT: 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 mouse mutant 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 absence of complex IV. Additionally, we also generated a COA3Y72C mouse, affected in COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides mechanistic insight into how defective mitochondrial gene expression causes tissue-specific inflammation.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Svenja Victoria Kaufmann

LAB HEAD: Henning Urlaub

PROVIDER: PXD041783 | Pride | 2024-07-25

REPOSITORIES: Pride

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			Action	DRS
	MR_SVK_P_Rehling_231122_151222_Fusion_Hepatocyte_TMT6_bRP_rep1_1.raw	Raw
	MR_SVK_P_Rehling_231122_151222_Fusion_Hepatocyte_TMT6_bRP_rep1_10.raw	Raw
	MR_SVK_P_Rehling_231122_151222_Fusion_Hepatocyte_TMT6_bRP_rep1_11.raw	Raw
	MR_SVK_P_Rehling_231122_151222_Fusion_Hepatocyte_TMT6_bRP_rep1_12.raw	Raw
	MR_SVK_P_Rehling_231122_151222_Fusion_Hepatocyte_TMT6_bRP_rep1_13.raw	Raw

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Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver

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

Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in liver

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

Complexome profiling of human cybrids laking mitochondrial genes Cox1 or Cox2

Project description:Mitochondrial respiratory chain (MRC) complexes I, III and IV are associated into large molecular structures named supercomplexes (SCs) or respirasomes, whose functional roles remain to be fully understood. Biochemical analyses in a diversity of OXPHOS-deficient cellular and animal models support the idea that one of the SCs function is to confer stability to individual MRC complexes, in particular to complex I (CI). To gain insight into the mechanisms that regulate the structural interdependences among MRC complexes, we performed complexome profiling of human cybrids laking mitochondrial genes Cox1 or Cox2 and compared protein assemblies and intermediates to control 143B cells.

2020-07-01 | PXD017840 | Pride

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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

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression

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.

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Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression

2023-08-17 | GSE240576 | GEO

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression

2023-08-17 | GSE224817 | GEO

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression

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 fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified 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, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, 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.

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Amplicons of a ND5 mRNA segment to detect m1A1374 levels in HEK APPwt and Ctl cells

Project description:This experiment was set up to quantify m1A methylation levels at position 1374 of the mitochondrial encoded ND5 mRNA. To investigate the relevance of this methylation in Alzheimer's disease two cell lines were compared. HEK APPwt cells, transfected with a plasmid encoding the wild-type Amyloid-Precursor-protein and untransfected control cells were used. In the first step a RT was performed with SuperScript-IV (SS-IV) and a ND5 specific RT primer. Afterwards a PCR was conducted to amplify the sequence around the m1A position. The amplicon is about 100 bp length and was sequenced in an Illumina Sequencing was performed in a MiSeq 2x75 PE run. For both cell lines the m1A analysis method was conducted with 4 biological replicates of total RNA and 2 biological replicates of RNA isolated from mitochondrial extracts.

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Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function

Project description:Short chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short chain enoyl-CoA esters to short chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell ‘knockout’ model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 ‘knockout’ cells showed reductions in key mitochondrial pathways, including the TCA cycle, receptor mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 ‘knockout’ cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 ‘knockout’ cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2, complex IV, complex V and supercomplexes CIII2/CIV and CI/CIII2/CIV). Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2, CIV, CV and the CI/CIII2/CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.

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