Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation. Lysosomal clearance is also compromised in MEFs harboring a p97 mutation that causes inclusion body myopathy and neurodegeneration, and damaged lysosomes accumulate in affected patient tissue carrying the mutation. Moreover, we show that p97 helps clear late endosomes/lysosomes ruptured by endocytosed tau fibrils. Thus, our data reveal an important mechanism of how p97 maintains lysosomal homeostasis, and implicate the pathway as a modulator of degenerative diseases.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242375 | PMC |
http://dx.doi.org/10.15252/embj.201695148 | DOI Listing |
Anal Chim Acta
February 2025
School of Chemistry and Chemical Engineering, Anhui University, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Key Laboratory of Structure and Functional Regulation of Hybrid Materials (Anhui University) Ministry of Education, Hefei, 230601, PR China; School of Chemical and Environmental Engineering, Anhui Polytechnic University, 241000, Wuhu, PR China. Electronic address:
A pivotal pathway of photodynamic therapy (PDT) is to prompt mitochondrial damage by reactive oxygen species (ROS) generation, thus leading to cancer cell apoptosis. However, mitochondrial autophagy is induced during such a PDT process, which is a protective mechanism for cancer cell homeostasis, resulting in undermined therapeutic efficacy. Herein, we report a series of meticulously designed donor (D)-π-acceptor (A) photosensitizers (PSs), characterized by the strategic modulation of thiophene π-bridges, which exhibit unparalleled mitochondrial targeting proficiency.
View Article and Find Full Text PDFRedox Biol
January 2025
Department of Reproductive Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China; Department of Reproductive Medicine, Affiliated Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China. Electronic address:
Oocyte aging is closely related to a decline in female fertility, accompanied by increased reactive oxygen species levels and changes in protein posttranslational modifications. However, the role of protein palmitoylation in oocyte aging has not been investigated. In the present study, a new association between redox and palmitoylation in aging oocytes was found.
View Article and Find Full Text PDFInt J Mol Sci
January 2025
Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy.
Pompe disease is a neuromuscular disorder caused by a deficiency of the enzyme acid alpha-glucosidase (), which leads to lysosomal glycogen accumulation and progressive development of muscle weakness. Two distinct isoforms have been identified. In the infantile form, the weakness is often severe and leads to motor difficulties from the first few months of life.
View Article and Find Full Text PDFBiomolecules
January 2025
Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University, 00185 Rome, Italy.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids and glucose. The accumulation of misfolded proteins triggers the release, stabilization, and nuclear translocation of NRF2, which in turn enhances the expression of critical components of both the proteasomal and lysosomal degradation pathways. This process facilitates the clearance of toxic protein aggregates, thereby actively maintaining cellular proteostasis.
View Article and Find Full Text PDFAdv Ther
January 2025
Cytel, Inc., Waltham, MA, USA.
Introduction: Fabry disease (FD) is a rare lysosomal storage disorder that is associated with pain and progressive damage to the renal, cardiac, and cerebrovascular systems. Enzyme replacement therapy (ERT) is one of the treatment options for FD and the most recently approved ERT agent, pegunigalsidase alfa, has shown clinical efficacy in three phase 3 clinical trials of adults with FD: BALANCE, BRIDGE, and BRIGHT. Recent published guidelines support the mapping of health utility state data to the EuroQol-5 Dimension-3 Level (EQ-5D-3L) index to align with the preferred methodology used by the National Institute for Health and Care Excellence (NICE).
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!