PXD073846

PXD073846 is an original dataset announced via ProteomeXchange.

Title	mtDNA alterations determine myoblast differentiation and disrupt skeletal muscle architecture
Description	Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage has been associated with the progressive decline of multiple tissues during aging. Muscle satellite cells (MuSCs), which sustain skeletal muscle regeneration throughout life, exhibit reduced number and regenerative capacity with age. Yet, the contribution of mtDNA mutations to MuSC integrity and their impact on skeletal muscle remain poorly understood. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (K320E) to induce mtDNA alterations in C2C12 myoblasts and MuSCs and investigated myogenic differentiation. During C2C12 differentiation, impaired mtDNA integrity disrupted respiratory complex assembly, increased reactive oxygen species, and directly compromised proper differentiation. Proximity proteomics in C2C12 differentiated cells revealed that K320E expression not only affects mtDNA encoded proteins, but also reshapes the complete mitochondrial proteome. In vivo, using the fluorescent reporter mitoTIMER, we found that mtDNA alterations in MuSCs, increased mitochondrial oxidation at early stages of differentiation, which normalized at later stages. Finally, by mimicking the age-dependent accumulation of mtDNA alterations, we show that mtDNA defects in MuSCs are transmitted to mature skeletal muscle. These defects induced architectural changes in muscle, including a glycolytic-to-oxidative fiber type transition reminiscent of aging human muscle. Together, our results establish a mechanistic link between mtDNA instability in muscle progenitors and aging of the skeletal muscle. With these results, we demonstrate that alterations in the mtDNA of muscle progenitors are sufficient to drive long-term changes in muscle architecture that may contribute to age-dependent functional decline.
HostingRepository	PRIDE
AnnounceDate	2026-08-17
AnnouncementXML	Submission_2026-08-17_00:48:33.681.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Pla Martin
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-30 08:57:37	ID requested
⏵ 1	2026-08-17 00:48:34	announced

Dataset with its publication pending

submitter keyword: Satellite Cells, Mitochondria, muscle differentiation,mtDNA, Skeletal Muscle

David Pla-Martin
contact affiliation	Institute of Biochemistry and Molecular Biology I, University Clinics and Faculty of Medicine, Heinrich-Heine University Düsseldorf, Germany
contact email	plamartin@hhu.de
lab head
David Pla Martin
contact affiliation	UKD-HHU
contact email	plamartin@hhu.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD073846
     1. Label: PRIDE project
     2. Name: mtDNA alterations determine myoblast differentiation and disrupt skeletal muscle architecture