Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2

Acta Neuropathologica · 15 authors, 11 centres

AI SUMMARY

FIDELITY 100%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This multi-center study investigated muscle biopsies from patients with myotonic dystrophy type 2 (DM2) using multiple analytical techniques. The central result is the identification of mitochondrial dysfunction, characterized by reduced respiratory chain complex proteins, lower mtDNA copy numbers, and impaired mitophagy.

Full summary

928 CHARS

This multi-center study analyzed muscle biopsy specimens from two independent cohorts of patients with myotonic dystrophy type 2 (DM2). Researchers employed histological, ultrastructural, molecular, proteomic, and transcriptomic analyses. The study revealed mitochondrial dysfunction, evidenced by morphological abnormalities, proteomic downregulation of respiratory chain complexes I, III, and IV, and significantly reduced mtDNA copy numbers. Transcriptomic data showed concordant reduction in mRNA for mitochondrial components. Evidence also suggested impaired mitophagy, as indicated by immunofluorescence patterns of LC-3, p62, and BNIP3. Limitations include the observational design without functional assays and the inability to confirm muscle-specific mtDNA deletions. The findings suggest mitochondrial pathology is a feature of DM2, potentially offering novel treatment targets, though functional validation is needed.

STUDY TYPE

other

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10799095

Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2

Acta Neuropathologica

READ THE FULL PAPER

ABSTRACT

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-023-02673-y.

CITATION EXPORT

Felix Kleefeld, Rita Horvath, Iago Pinal-Fernandez et al.. Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2. Acta Neuropathologica. (2024). https://doi.org/10.1007/s00401-023-02673-y

AUTHORS

15 · 11 CENTRES

Felix Kleefeld, Rita Horvath, Iago Pinal-Fernandez, Andrew L. Mammen, Maria Casal-Dominguez, Denisa Hathazi, Sarah Melchert, Katrin Hahn, Albert Sickmann, Claudia Muselmann-Genschow, Andreas Hentschel, Corinna Preuße, Andreas Roos, Benedikt Schoser, Werner Stenzel

1grid.6363.00000 0001 2218 4662Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health (BIH), Charitéplatz 1, 10117 Berlin, Germany
2https://ror.org/013meh722grid.5335.00000 0001 2188 5934Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
3grid.420086.80000 0001 2237 2479Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 USA
4grid.21107.350000 0001 2171 9311Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
5grid.6363.00000 0001 2218 4662Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
6https://ror.org/02jhqqg57grid.419243.90000 0004 0492 9407Leibniz-Institut Für Analytische Wissenschaften-ISAS E.V., 44139 Dortmund, Germany
7grid.6363.00000 0001 2218 4662Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health (BIH), Charitéplatz 1, 10117 Berlin, Germany
8grid.6363.00000 0001 2218 4662Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health (BIH), Augustenburger Platz 1, 13353 Berlin, Germany
9grid.5718.b0000 0001 2187 5445Pediatric Neurology, Faculty of Medicine, University Children’s Hospital, University of Duisburg-Essen, Essen, Germany
10grid.28046.380000 0001 2182 2255Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1 Canada
11https://ror.org/05591te55grid.5252.00000 0004 1936 973XDepartment of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany