An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.
Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic si...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-03-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3001977 |
| _version_ | 1797848166445350912 |
|---|---|
| author | Natalia Moskal Naomi P Visanji Olena Gorbenko Vijay Narasimhan Hannah Tyrrell Jess Nash Peter N Lewis G Angus McQuibban |
| author_facet | Natalia Moskal Naomi P Visanji Olena Gorbenko Vijay Narasimhan Hannah Tyrrell Jess Nash Peter N Lewis G Angus McQuibban |
| author_sort | Natalia Moskal |
| collection | DOAJ |
| description | Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage. |
| first_indexed | 2024-04-09T18:24:09Z |
| format | Article |
| id | doaj.art-453ac47e8c7f46c98583cd00bf0689b9 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-09T18:24:09Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-453ac47e8c7f46c98583cd00bf0689b92023-04-12T05:30:45ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-03-01213e300197710.1371/journal.pbio.3001977An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.Natalia MoskalNaomi P VisanjiOlena GorbenkoVijay NarasimhanHannah TyrrellJess NashPeter N LewisG Angus McQuibbanFailures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.https://doi.org/10.1371/journal.pbio.3001977 |
| spellingShingle | Natalia Moskal Naomi P Visanji Olena Gorbenko Vijay Narasimhan Hannah Tyrrell Jess Nash Peter N Lewis G Angus McQuibban An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. PLoS Biology |
| title | An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. |
| title_full | An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. |
| title_fullStr | An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. |
| title_full_unstemmed | An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. |
| title_short | An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets. |
| title_sort | ai guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets |
| url | https://doi.org/10.1371/journal.pbio.3001977 |
| work_keys_str_mv | AT nataliamoskal anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT naomipvisanji anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT olenagorbenko anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT vijaynarasimhan anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT hannahtyrrell anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT jessnash anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT peternlewis anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT gangusmcquibban anaiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT nataliamoskal aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT naomipvisanji aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT olenagorbenko aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT vijaynarasimhan aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT hannahtyrrell aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT jessnash aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT peternlewis aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets AT gangusmcquibban aiguidedscreenidentifiesprobucolasanenhancerofmitophagythroughmodulationoflipiddroplets |