TY - JOUR
T1 - PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage
AU - Lambourne, Olivia A.
AU - Bell, Shane
AU - Wilhelm, Léa P.
AU - Yarbrough, Erika B.
AU - Holly, Gabriel G.
AU - Russell, Oliver M.
AU - Alghamdi, Arwa M.
AU - Fdel, Azeza M.
AU - Varricchio, Carmine
AU - Lane, Emma L.
AU - Ganley, Ian G.
AU - Jones, Arwyn T.
AU - Goldberg, Matthew S.
AU - Mehellou, Youcef
N1 - Funding Information:
This work was supported by a PhD studentship awarded to O.A.L by Cardiff School of Pharmacy and Pharmaceutical Sciences and a Wellcome Trust ISSF3 grant awarded to Y.M., E.L.L., and A.T.J. (ref. AC1800IF11). I.G.G. was funded by a grant from the Medical Research Council, UK (MC_UU_00018/2). S.B. and O.M.R. were funded by the Wellcome Trust (203105/Z/16/Z).
Copyright:
© 2023 The Authors. Published by American Chemical Society
PY - 2023/6/8
Y1 - 2023/6/8
N2 - Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such as N6-(2-furanylmethyl)adenosine (known as kinetin riboside) and N6-benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m-chlorophenyl-hydrazine and niclosamide. Together, this highlights N6-substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.
AB - Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such as N6-(2-furanylmethyl)adenosine (known as kinetin riboside) and N6-benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m-chlorophenyl-hydrazine and niclosamide. Together, this highlights N6-substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.
UR - http://www.scopus.com/inward/record.url?scp=85162232355&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00555
DO - 10.1021/acs.jmedchem.3c00555
M3 - Article
C2 - 37248632
SN - 0022-2623
VL - 66
SP - 7645
EP - 7656
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -