PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission

Abstract

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

Cocaine perturbs mitovesicle biology in the brain

“…Accordingly, we analyzed the levels of a master regulator of mitochondrial fission, DRP1, as well as its activation status (p-DRP1, serine 616), in the brain homogenates of mice chronically treated with cocaine. When phosphorylated at position 616, DRP1 is activated, leading to higher mitochondrial fission and potentially neuronal death, as has been extensively demonstrated (Chandra et al, 2017;Gao et al, 2022;D. I. Kim et al, 2016;Luo et al, 2017;Roe & Qi, 2018).…”

Upregulated extracellular matrix-related genes and impaired synaptic activity in dopaminergic and hippocampal neurons derived from Parkinson’s disease patients withPINK1andPARK2mutations

“…The hippocampus plays a crucial role in cognition, including learning and memory 71 . In mouse models of PINK1 and PARK2 mutations, synaptic development and glutamatergic synaptic transmission were impaired in hippocampal neurons [72][73][74] . These alterations in synaptic activity in hippocampal neurons, as observed in our study, may contribute to the cognitive decline observed in the patients.…”

Investigating the effects of 7‐ketocholesterol on retinal pigment epithelium bioenergetics

“…The loss of PINK1 was demonstrated to impair mitochondrial fission, causing defective assembly of the electron transport chain complexes in drosophila 56 . Moreover, PINK1 has been reported to directly phosphorylate DRP1 Ser616 to promote mitochondrial fission, separating the damaged mitochondria from the healthy ones 57,58 . Interestingly, our results demonstrate a dose‐dependent increase in PINK1 expression upon 7KC exposure.…”