PXD047527

PXD047527 is an original dataset announced via ProteomeXchange.

Title	Assembly of respiratory complex I is regulated by FMN insertion into the N-module.
Description	Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a known N-site inhibitor, uniquely affects the stability of complex I by inhibiting its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the accumulation of assembly intermediates that lack the N-module. Remarkably, high-dose DPI treatment can completely and reversibly degrade complex I in different cellular models. The mechanism involves the accumulation of DPI in mitochondria, where it reacts with FMN, depleting the effective pool of FMN and halting complex I maturation. Consistently, growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial FAD carrier gene SLC25A32 results in complex I degradation and impairs complex I-dependent respiration. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_10:31:44.112.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enrique Calvo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-05 02:30:37	ID requested
⏵ 1	2024-01-26 10:31:45	announced

Curtabbi A, Guar, á, s A, Cabrera-Alarc, ó, n JL, Rivero M, Calvo E, Rosa-Moreno M, V, á, zquez J, Medina M, Enr, í, quez JA, Regulation of respiratory complex I assembly by FMN cofactor targeting. Redox Biol, 69():103001(2024) [pubmed]

10.1016/j.redox.2023.103001;

submitter keyword: human Nmodule

Enrique Calvo
contact affiliation	CNIC
contact email	ecalvo@cnic.es
lab head
Enrique Calvo
contact affiliation	CNIC
contact email	ecalvo@cnic.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD047527

PRIDE project URI

• PRIDE
  1. PXD047527
     1. Label: PRIDE project
     2. Name: Assembly of respiratory complex I is regulated by FMN insertion into the N-module.