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Lysosomal damage-induced secretion of macromolecular complexes in HeLa cells by label-free proteomics

ABSTRACT: HeLa cells were treated with LLOMe to induce lysosomal membrane permeabilization. Conditioned media were collected, and secreted macromolecular complexes were enriched by ultracentrifugation at 100,000 × g. The protein content was analyzed by label-free, non-quantitative LC-MS/MS to identify components of stress-induced extracellular protein assemblies.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zihan Zhao

PROVIDER: PXD080292 | iProX | Sat Jun 27 00:00:00 BST 2026

REPOSITORIES: iProX

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Project 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.

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Lysosomal damage-induced secretion of macromolecular complexes in HeLa cells by label-free proteomics

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