Objective: To characterize the response of cells treated with Gamitrinib-triphenylphosphonium (G-TTP) a mitochondrial targeted inhibitor of the chaperone Hsp90.

Background: Upon dissipation of the mitochondrial membrane potential the recessive PD genes PINK1 and Parkin together mediate a protective response pathway to eliminate dysfunctional mitochondria by autophagy. This pathway is also activated upon accumulation of unfolded mitochondrial proteins that is induced by overexpression of deltaOTC or reduced function of the chaperone mortalin. Here, we characterized the response of cells treated with the mitochondria-targeted small molecule inhibitor G-TTP that inhibits the molecular chaperone HSP90.

Methods: We used a combination of biochemical methods and (conventional and High Content) imaging techniques to measure PINK1 and Parkin activation and downstream activities in HeLa cells, in skin fibroblasts and in induced neurons (iNeurons) from PINK1 patients and controls. qRT-PCR was used to measure the induction of genes commonly upregulated during the mitochondrial unfolded protein response (mitoUPR).

Results: We found that G-TTP but not the non mitochondria targeted HSP90 inhibitor 17-AAG induced PINK1 stabilization and Parkin recruitment to mitochondria. This was accompanied by the accumulation of the mitophagy label pS65-ubiquitin and different autophagy receptors at mitochondria.

Conclusions: It has been suggested that the accumulation of mitochondrial unfolded proteins is a physiological trigger of mitophagy. Our results indicate that G-TTP can be used to induce this response pharmacologically.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mitochondrial-hsp90-inhibitor-g-ttp-triggers-pink1parkin-dependent-mitochondrial-quality-control/