AI-guided screen identifies probucol-mediated mitophagy enhancement through modulation of lipid droplets

Abstract

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 under basal conditions by probucol treatment in addition to increased contact between lipid droplets and mitochondria. Conversely, lipid droplet expansion, which occurs following mitochondrial damage was suppressed by probucol and probucol-mediated mitophagy enhancement required lipid droplets. Probucol-mediated lipid droplet dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.

Mechanism of Ubiquitin Ligase Activation of Parkin by a Small Molecule Molecular Glue

“…Inhibitors of USP30, a deubiquitinating enzyme on the OMM that counters parkin's activity 41 , are also being developed by several companies and are currently under clinical evaluation. Other groups used phenotypic screens or computational approaches to identify small molecules that stimulate parkin/PINK1mediated mitophagy, but the targets of these molecules remain unknown 42,43 . Parkinactivating compounds have also been pursued by several groups, with three patents reporting small-molecules that activate parkin-mediated mitophagy [44][45][46] .…”