PXD058344-1

PXD058344 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial Protein Import Stress Causes Lysosomal Damage and Tissue Atrophy
Description	Mitochondrial abnormalities are commonly associated with aging-related degenerative disease and the atrophy of tissues including muscle and brain. Whether bioenergetic defect is the sole pathogenic factor has been long questioned. Lysosomal damage is another hallmark of degenerative disease. However, it is unknown whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. Here, we show that mitochondrial protein import stress, which can be induced by many forms of mitochondrial injuries, causes structural and functional damage to the yeast vacuole and its mouse counterpart, the lysosome. This effect is independent of bioenergetic defects and the production of reactive oxygen species. We found that unimported mitochondrial proteins are targeted to the vacuole for degradation in yeast. Overloading by these proteins causes V-ATPase disassembly, and vacuolar deacidification, fragmentation and membrane permeabilization. In a mouse model of mitochondrial protein import stress and muscle atrophy induced by overloading of the mitochondrial protein ANT1, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, nucleotide biosynthesis, lysosomal biogenesis and iron homeostasis are activated. These signatures are recapitulated in yeast mutants of severe vacuolar damage. Supporting lysosomal dysfunction, the Ant1-transgenic muscles accumulate glycogens, lipofuscins and poorly processed multiple vesicle bodies. Multiple lysosomal repair and lysophagic pathways are activated. Luminal proteolytic enzymes including cathepsins are released into the cytosol, which likely contributes to imbalanced cellular proteostasis, reduced myofiber size and progressive muscle atrophy. In summary, we show an evolutionarily conserved pathway wherein mitochondrial defect can epistatically cause proteostatic damage to the lysosome thereby leading to tissue atrophy. This finding could help the better understanding of how the mitochondrial and lysosomal pathways of pathogenesis interact to cause degenerative disease.
HostingRepository	PRIDE
AnnounceDate	2026-03-27
AnnouncementXML	Submission_2026-03-27_08:37:40.374.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD058344
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Ebbing de Jong
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-27 10:49:33	ID requested
⏵ 1	2026-03-27 08:37:40	announced

10.6019/PXD058344;

submitter keyword: mPOS,Mouse, muscle atrophy, mitochondria

Xin Jie Chen
contact affiliation	Department of Biochemistry&Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
contact email	chenx@upstate.edu
lab head
Ebbing de Jong
contact affiliation	SUNY Upstate Medical University
contact email	dejonge@upstate.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058344
     1. Label: PRIDE project
     2. Name: Mitochondrial Protein Import Stress Causes Lysosomal Damage and Tissue Atrophy