Dataset Information

Mitochondrial leakage and mtDNA damage triggering early immune response in Inclusion Body Myositis.

ABSTRACT: Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy (IIM). Significant molecular similarities have been recently detected between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to full-blown IBM, and prompting the inclusion of PM-Mito as an early form of IBM (eIBM) within the IBM spectrum. Both early and late stages of IBM show mitochondrial abnormalities, suggesting mitochondrial dysfunction is an early feature of IBM. The primary objective of this study was to characterize the mitochondrial phenotype in eIBM/PM-Mito at histological, ultrastructural, and molecular levels and to study the possible interplay between mitochondrial dysfunction and inflammation. Skeletal muscle biopsies of 27 patients with eIBM/PM-Mito and 27 full-blown IBM were included for morphological and ultrastructural analysis. Mitochondrial DNA (mtDNA) copy number and deletions were assessed by qPCR and long-range PCR, respectively. In addition, full-length single-molecule sequencing of the mtDNA enabled precise mapping of deletions. Protein and RNA levels were studied using unbiased proteomic profiling, immunoblotting, and bulk RNA sequencing. Cell-free mtDNA (cfmtDNA) was measured in the serum of full-blown IBM patients.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle

SUBMITTER: Andreas Hentschel

LAB HEAD: Albert Sickmann

PROVIDER: PXD053742 | Pride | 2026-04-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20240415_111102_PMmito_IBM_ctrl_analysis.sne	Other
	Std-QExactive01-04983_NME_GPS_PM-Mito_N9401.raw	Raw
	Std-QExactive01-04984_NME_GPS_PM-Mito_N355315.raw	Raw
	Std-QExactive01-04985_NME_GPS_PM-Mito_N179619.raw	Raw
	Std-QExactive01-04986_NME_GPS_PM-Mito_N92819.raw	Raw

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Publications

Mitochondrial damage is associated with an early immune response in inclusion body myositis.

Kleefeld Felix F Cross Emily E Lagos Daniel D Walli Sara S Schoser Benedikt B Hentschel Andreas A Ruck Tobias T Nelke Christopher C Hahn Katrin K Hathazi Denisa D Mammen Andrew L AL Casal-Dominguez Maria M Gut Marta M Gut Ivo Glynne IG Heath Simon S Schänzer Anne A Goebel Hans-Hilmar HH Pinal-Fernandez Iago I Roos Andreas A Preuße Corinna C Stenzel Werner W Horvath Rita R

Brain : a journal of neurology 20250901 9

Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy. Recent findings demonstrated significant molecular similarities between PM-Mito and inclusion body myositis (IBM), suggesting a trajectory from early to late IBM and prompting the inclusion of PM-Mito as an IBM precursor (early IBM) within the IBM spectrum. Both PM-Mito and IBM show mitochondrial abnormalities, suggesting that mitochondrial disturbance is a crucial e ...[more]

PMID: 40193586

Similar Datasets

Project description:Idiopathic inflammatory myopathies (IIMs) encompass a diverse group of autoimmune disorders affecting skeletal muscle, including dermatomyositis (DM), anti-synthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Polymyositis with mitochondrial pathology (PM-Mito) has been proposed as a potential IIM subtype, with emerging evidence suggesting it may represent an early form of IBM. IBM is characterized by unique clinical features, such as insidious onset and resistance to immunotherapies, alongside hallmark histopathological findings, including rimmed vacuoles, cytoplasmic protein aggregates, CD8+ T cell-dominated inflammation, and prominent mitochondrial abnormalities. Mitochondrial dysfunction, ragged-red fibers, and disrupted oxidative phosphorylation are increasingly recognized as central contributors to IBM pathology, implicating mitochondrial processes in both muscle weakness and chronic inflammation. This study presents a longitudinal and cross-sectional proteomic analysis of IBM in comparison to other IIM subtypes. We identified both established and novel hallmarks of IBM, particularly highlighting mitochondrial dysfunction and immune dysregulation, while also examining PM-Mito as a potential precursor state to IBM. Using an unbiased mass spectrometry-based proteomic approach, we identified a distinct proteomic signature for IBM characterized by mitochondrial alterations and type II interferon-associated immune pathway dysregulation. PM-Mito samples displayed a dysregulation of immune regulatory proteins and mitochondrial pathways. This study reinforces the unique molecular profile of IBM compared to other IIM subtypes while strengthening the concept of a disease continuum between IBM and PM-Mito. By uncovering shared mitochondrial and immune dysregulation in IBM and PM-Mito, these findings support the notion that PM-Mito may represent an early or transitional stage of IBM, providing new insights into disease progression and potential therapeutic targets.

Project description:Purpose: To develop a pipeline (Splice-Break) for high-resolution quantification of mtDNA deletions, provide a catalogue of human mtDNA deletion breakpoints, and evaluate mtDNA deletions in brains from subjects with psychiatric disorders. Methods: 93 samples from human postmortem brain and blood were obtained from the Southwest Brain Bank (SBB) and University of California, Irvine (UCI) Brain Bank. Total DNA was extracted from frozen homogenate tissue and mtDNA was amplified/enriched using a single long-range PCR. Mitochondrial amplicons were purified by bead purification to retain both wild-type and deleted molecules (i.e., no gel excision was performed). mtDNA-enriched PCR amplicons were prepared for sequencing using standard Illumina protocols for DNA. Samples were sequenced 150-mer paired-end reads, in multiplex (96x per lane), on an unpatterned flowcell (HiSeq 2500). Fastq files were processed using our Splice-Break pipeline for the detection and relative quantification of mtDNA deletions. Results: A catalogue of 4,489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, was produced. Analyses of 93 samples from postmortem brain and blood found 1) the 4,977bp “common deletion” was neither the most frequent deletion nor the most abundant; 2) brain contained significantly more mtDNA deletions than blood; 3) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; 4) many individual deletions (and cumulative deletion metrics) had significant and positive correlations with age; and 5) the highest deletion burdens were observed in a subset of subjects with major depressive disorder (MDD), and these subjects had mtDNA deletion levels at or above those detected in typical deletion pathologies (e.g., Kearns-Sayre syndrome (KSS) muscle). Conclusions: Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.