Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

Abstract

PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in the mid‐2000s, when PINK1 mutations were found to cause early onset Parkinson's disease (PD). As most of the PD‐related mutations occurred in the kinase domain and impaired PINK1′s catalytic activity, it was suggested that small molecules that activated PINK1 would maintain mitochondrial quality control and, as a result, have neuroprotective effects. Working on this hypothesis, a few small‐molecule PINK1 activators that offer critical insights and distinct approaches for activating PINK1 have been discovered. Herein, we briefly highlight the discovery of these small molecules and offer insight into the future development of small‐molecule PINK1 activators as potential treatments for PD.

Mitochondrial Dysfunction and Mitophagy in Parkinson’s Disease: From Mechanism to Therapy

“…Similarly, although less defined, USP8, USP14, and USP15 inhibitors represent promising routes to upregulating mitophagy [20,76,77]. Direct activation of PINK1 has been demonstrated by kinetin triphosphate KTP [78] and further development of bioavailable KTP precursors is underway [79]. In addition, two smallmolecule activators of PINK1 which are structurally distinct from KTP have been identified by high-throughput screening and have been validated in both dopaminergic neurons and PINK1 knockdown Drosophila [80].…”

PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage

“…(a) Schematic representation of PINK1/Parkin signaling in healthy and damaged mitochondria. Figure reproduced from Lambourne and Mehellou 15 with some modifications. (b) Chemical structure of kinetin and its metabolism to generate the PINK1 ATP-neosubstrate, KR triphosphate.…”

The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

“…As PINK1 can be activated by the loss of mitochondrial membrane potential, another approach to indirectly increase the kinase activity of PINK1 could be to depolarise the mitochondrial membrane potential. This could be achieved using the proton ionophore, CCCP, carbonyl cyanide-4-phenylhydrazone (FCCP), the potassium uniporter valinomycin, or a combination of antimycin A and oligomycin A [79]. However, inherent cellular toxicity restricts their in vivo application.…”