Dataset Information

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

ABSTRACT: Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function.

SUBMITTER: Floyd BJ

PROVIDER: S-EPMC4992456 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

Floyd Brendan J BJ Wilkerson Emily M EM Veling Mike T MT Minogue Catie E CE Xia Chuanwu C Beebe Emily T ET Wrobel Russell L RL Cho Holly H Kremer Laura S LS Alston Charlotte L CL Gromek Katarzyna A KA Dolan Brendan K BK Ulbrich Arne A Stefely Jonathan A JA Bohl Sarah L SL Werner Kelly M KM Jochem Adam A Westphall Michael S MS Rensvold Jarred W JW Taylor Robert W RW Prokisch Holger H Kim Jung-Ja P JP Coon Joshua J JJ Pagliarini David J DJ

Molecular cell 20160804 4

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) asse ...[more]

PMID: 27499296

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Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion. Affymetrix Human Exon 1.0ST microarray analysis was performed on 29 skeletal muscle samples and Fibroblast cell lines from mitochondrial disease patients and age- and gender-matched controls.

Dataset Information

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

Publications

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

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