Mitochondrial respiratory complexes assemble into supercomplexes (SC). Q-respirasome (III + IV) requires the supercomplex assembly factor (SCAF1) protein. The role of this factor in the N-respirasome (I + III + IV) and the physiological role of SCs are controversial. Here, we study C57BL/6J mice harboring nonfunctional SCAF1, the full knockout for SCAF1, or the wild-type version of the protein and found that exercise performance is SCAF1 dependent. By combining quantitative data-independent proteomics, 2D Blue native gel electrophoresis, and functional analysis of enriched respirasome fractions, we show that SCAF1 confers structural attachment between III and IV within the N-respirasome, increases NADH-dependent respiration, and reduces reactive oxygen species (ROS). Furthermore, the expression of AOX in cells and mice confirms that CI-CIII superassembly segments the CoQ in two pools and modulates CI-NADH oxidative capacity.
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http://dx.doi.org/10.1126/sciadv.aba7509 | DOI Listing |
Nucleic Acids Res
December 2024
Institute of Biochemistry, University of Kiel, Rudolf-Höber-Straße 1, Kiel 24118, Germany.
Transcripts produced by RNA polymerase II (RNAPII) are fundamental for cellular responses to environmental changes. It is therefore no surprise that there exist multiple avenues for the regulation of this process. To explore the regulation mediated by RNAPII-interacting proteins, we used a small interfering RNA (siRNA)-based screen to systematically evaluate their influence on RNA synthesis.
View Article and Find Full Text PDFNat Commun
June 2024
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine.
View Article and Find Full Text PDFMol Cell Proteomics
August 2024
MRC Protein Phosphorylation and Ubiquitylation Unit and School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dundee, UK. Electronic address:
The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are both in clinical trials for the treatment of advanced solid tumors as monotherapy or in combination with genotoxic agents. We carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib, using an optimized mass spectrometry pipeline.
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May 2024
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms.
View Article and Find Full Text PDFDev Cell
July 2024
Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, Bern, Switzerland; Department for Biomedical Research, Cardiovascular Disease Program, University of Bern, Bern, Switzerland. Electronic address:
The oxidative phosphorylation (OXPHOS) system is intricately organized, with respiratory complexes forming super-assembled quaternary structures whose assembly mechanisms and physiological roles remain under investigation. Cox7a2l, also known as Scaf1, facilitates complex III and complex IV (CIII-CIV) super-assembly, enhancing energetic efficiency in various species. We examined the role of Cox7a1, another Cox7a family member, in supercomplex assembly and muscle physiology.
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