PXD048004

PXD048004 is an original dataset announced via ProteomeXchange.

Title	A pathogenic role for mitochondrial dysfunction and oxidative stress in myositis
Description	Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.
HostingRepository	PRIDE
AnnounceDate	2024-05-31
AnnouncementXML	Submission_2024-05-31_01:57:45.971.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Clement GUILLOU
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-20 06:51:33	ID requested
⏵ 1	2024-05-31 01:57:46	announced

Dataset with its publication pending

submitter keyword: LC-MSMS, mitochondrial dysfnoction,Icos KO NOD mice

ABAD Catalina
contact affiliation	Rouen Normandy University, INSERM U1234 PAnTHER, Rouen, FRANCE
contact email	catalina.abad@inserm.fr
lab head
Clement GUILLOU
contact affiliation	PISSARO Proteomics Platform, University of Rouen
contact email	clement.guillou1@univ-rouen.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048004
     1. Label: PRIDE project
     2. Name: A pathogenic role for mitochondrial dysfunction and oxidative stress in myositis