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Respiratory chain protein analysis and gene expression profiles of fibroblast cell lines from 9 patients with SURF1 gene mutations

ABSTRACT: Upregulation of CI, CIII and CV at a protein but not mRNA level in LSCOX cell with COX deficiency due to SURF1 mutations compared to control – evidence for posttranscriptional compensatory mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26322 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA136773

REPOSITORIES: GEO

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Respiratory chain protein analysis and gene expression profiles of fibroblast cell lines from 9 patients with SURF1 gene mutations

Project description:Upregulation of CI, CIII and CV at a protein but not mRNA level in LSCOX cell with COX deficiency due to SURF1 mutations compared to control – evidence for posttranscriptional compensatory mechanism. Two-condition experiment, patients vs. controls cells. Biological replicates: 3 controls and 9 patients, independently grown and harvested.

2011-06-01 | E-GEOD-26322 | biostudies-arrayexpress

Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis

Project description:The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependence of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV, COX) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process are disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII and cIV were missing in COX4 KO due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labelling of mtDNA-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates indicating that cI biogenesis, rather than stability, was the affected process. We propose, that impairment of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms which may couple biogenesis of cI and cIV.

2021-02-18 | PXD023367 | Pride

Normal respiratory chain capacity and physiology in mice with severely reduced levels of mitochondrial respirasomes; Cross-linking of intact mitochondria

Project description:The mammalian oxidative phosphorylation (OXPHOS) system in the inner mitochondrial membrane comprises respiratory chain complexes I-IV (CI-CIV) and ATP synthase. Together, these protein complexes harvest metabolic energy to generate ATP, the cellular energy currency. The inner mitochondrial membrane is abundant in OXPHOS complexes and CI, CIII and CIV exhibit specific protein-protein interactions to form stable supercomplex assemblies, exemplified by the respirasome (CI-CIII2-CIV). Respirasomes are conserved in evolution, and as well documented by biochemical and structural methods. However, their physiological roles are much debated, despite a substantial literature suggesting their importance in facilitating catalysis and regulating turnover in response to metabolic demand. To investigate the in vivo role of respirasomes, we deleted a short conserved, charged loop in the UQCRC1 subunit of CIII that contacts CI. The resulting homozygous knock-in mice show profoundly decreased levels of respirasomes on blue native polyacrylamide gel electrophoresis (BN-PAGE) and complexome profiling proteomics analyses of different tissues, although the individual complexes appear unaffected. In vivo The spatial organization of respirasomes in vivo was altered in knock-in mice as shown by cross-linking experiments on intact mitochondria. Surprisingly, the mutant mice are healthy, with normal respiratory chain capacity and normal exercise tolerance. Therefore, respirasomes are dispensable for OXPHOS function in vivo.

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Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

Project description:Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Coenzyme Q: cytochrome c oxidoreductase (complex III or CIII) occupies a central position in the ETC, receiving electrons from diverse fuel sources to control the ubiquinol:ubiquinone (CoQH2/CoQ) ratio. As such, CIII is an attractive node for controlling ETC biogenesis during metabolic stress. Here, we report the discovery of mammalian CoOrdinator of Mitochondrial CYTB or “COM” complexes that regulate CIII biogenesis in a step-wise fashion in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and the membrane anchor C16ORF91 (UQCC4), facilitates the translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN, together with COMA subunits form the COMB complex that stabilizes nascent CYTB. Finally, UQCC3-containing COMC promotes CTYB maturation and association with downstream CIII subunits. This stepwise assembly enables cells to adapt to metabolic stress by increasing CIII biogenesis and inducing an integrated stress response when challenged. Furthermore, when nuclear CIII subunits are unavailable for assembly, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis, and uncover the roles of mito-SEPs in mitochondrial homeostasis during energy stress.

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Lifelong Reduction in Complex IV Induces Tissue Specific Metabolic Effects But Does Not Reduce Lifespan or Healthspan in Mice

Project description:Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity and mitochon-drial biogenesis) in Surf1-/- mice. The lack of deleterious phenotypes in Surf1-/- mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (non-significant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1-/- vs Surf1+/+ mice despite substantial decreases in COX activity (22-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1-/- mice (36 and 19%, respectively). We measured gene expression, metabolites and targeted expression of key metabolic proteins in adi-pose tissue, liver and brain in Surf1+/+ and Surf1-/- mice. Gene expression was differentially regulated in a tissue specific pattern. We found that many proteins and metabolites are downregulated in Surf1-/- adipose tissue and reversed by DR, while in brain most metabolites that changed were elevated in Surf1-/- mice. Finally, mitochondrial unfolded protein response (UPRmt)-associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or the response to reduced COX activity. While the changes in gene expression and metabolism may represent com-pensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1-/- mice, suggesting that mitochondrial deficiencies may not be a critical determinant of lifespan.

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Leigh Syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing.

Project description:Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the hSurf1 gene. LSSurf1 patients show a marked and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). hSurf1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a D. melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of hSurf1. Knock down of Surf1 was induced (i) ubiquitously, which led to larval lethality; (ii) in the mesodermal derivatives, which led to pupal lethality; (iii) in the central nervous system, which allowed survival; and (iv) at specific developmental stages. A biochemical characterization was carried out in knock down individuals, which unexpectedly revealed defects in all complexes of the mitochondrial respiratory chain (MRC) included the F-ATP synthase (complex V) in larvae, and a COX-specific impairment in adults. Silencing of Surf1 expression in Drosophila S2R+ cells led to loss of COX activity associated with decreased oxygen consumption. We conclude that Surf1 is essential for COX activity and mitochondrial function in D. melanogaster, and provide a new tool to clarify the pathogenic mechanisms of LS.

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