Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function.
| Title: | Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function. |
|---|---|
| Authors: | Qin Y; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Teker SS; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; La Cunza N; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.; Tong Y; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.; Theusch E; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Yang NV; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA.; Venkatesan L; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Su J; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Wang X; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Krauss RM; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.; Liver Center, University of California San Francisco, San Francisco, CA, USA.; Lakkaraju A; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Mattis AN; Liver Center, University of California San Francisco, San Francisco, CA, USA.; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Medina MW; Department of Pediatrics, University of California San Francisco, Oakland, CA, USA. marisa.medina@ucsf.edu.; Liver Center, University of California San Francisco, San Francisco, CA, USA. marisa.medina@ucsf.edu.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. marisa.medina@ucsf.edu. |
| Source: | Cell death & disease [Cell Death Dis] 2026 Jan 09; Vol. 17 (1), pp. 26. Date of Electronic Publication: 2026 Jan 09. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : Nature Pub. Group |
| MeSH Terms: | Lipid Metabolism*/genetics ; Autophagy*/genetics ; Mitochondria*/metabolism ; Fatty Liver*/metabolism ; Fatty Liver*/pathology ; Fatty Liver*/genetics ; Membrane Proteins*/metabolism ; Membrane Proteins*/genetics ; Membrane Proteins*/deficiency; Lysosomes/metabolism ; Animals ; Humans ; Mice ; Oxidative Stress ; Mitophagy ; Mice, Knockout |
| Abstract: | Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning, which is critical for lysosome fusion with the autophagosome, but is less well studied. Here, we demonstrate that the absence of TMEM55B in murine models accelerates MASLD onset and progression to metabolic dysfunction-associated steatohepatitis (MASH). In cellular models, TMEM55B deficiency enhances incomplete lipophagy, whereby lysosome-lipid droplet interactions are increased, but lysosomal cargo is not fully degraded and/or released, leading to the development of lipid-filled lysosomes (lipolysosomes). Loss of TMEM55B also impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that targeting lipophagy for MASLD therapeutic development should be carefully considered to ensure promotion of the entire lipophagic flux pathway and whether it occurs in the context of mitochondrial dysfunction.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: A.N.M. is a consultant for BioMarin Pharmaceuticals, Pliant Therapeutics, Regeneron Pharmaceuticals, and HepaTx. Ethics: All animal procedures were performed under NIH guidelines and with full institutional approval from the IACUC at UCSF. |
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| Grant Information: | R01 HL139902 United States HL NHLBI NIH HHS; NIH R01 EY030668 U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER); P30 DK026743 United States DK NIDDK NIH HHS; R01EY030668S1 U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI); NIH R01 EY030668 U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI); R01 EY030668 United States EY NEI NIH HHS; R01 DK130391 United States DK NIDDK NIH HHS; R56 DK135259 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 0 (Membrane Proteins) |
| Entry Date(s): | Date Created: 20260109 Date Completed: 20260625 Latest Revision: 20260625 |
| Update Code: | 20260626 |
| PubMed Central ID: | PMC12789068 |
| DOI: | 10.1038/s41419-025-08210-x |
| PMID: | 41513622 |
| Database: | MEDLINE |
Journal Article