Pink1-mediated Parkin activation is insufficient to allow Parkin binding to dysfunctional mitochondria in NME3-defective cells. NME3-regulated lipid signal separates mitochondria from endoplasmic reticulum tethering for PINK1-mediated Parkin binding on depolarized mitochondria.
In familial autosomal recessive early-onset Parkinson disease, PINK1 and Parkin have been identified as the causative genes. The accumulation of dysfunctional mitochondria is toxic to neuron. The loss of mitochondrial membrane potential is a sign of their malfunction.
It is well established that PINK1 is activated and accumulated on the depolarized outer mitochondrial membrane, by which Parkin is activated on mitochondria to degrade depolarized mitochondria through ubiquitin-dependent degradation. This process ensures the quality control of mitochondria to maintain neuron function.
This study, published in Autophagy, uncovered that Pink1-mediated Parkin activation is insufficient to allow Parkin binding to depolarized mitochondria in NME3-defective cells. NME3 is a member of the nucleoside diphosphate kinase family located on mitochondrial outer membrane. NME3 deficiency is associated with neurodegenerative disorder in a fatal newborn.
Our mechanistic investigation reveals that NME3 cooperates with mitoPLD to convert cardiolipin, a unique mitochondrial lipid, to phosphatidic acid on depolarized mitochondrial surface. This lipid signal promotes the separation of mitochondria from endoplasmic reticulum tethering, allowing PINK1 to phosphorylate ubiquitin (Ub) of poly-Ub-chain conjugated on MFN2 on mitochondrial outer membrane.
Parkin is a cytosolic ubiquitin E3 ligase, normally inactive due to its autoinhibitory conformation. Already known is that PINK1 activation on depolarized mitochondria relieves the autoinhibitory conformation of Parkin by phosphorylating Parkin and Ub.
“Therefore, our finding in the requirement of NME3-regulated phosphatidic acid for PINK1-mediated Ub phosphorylation in poly-Ub chains on MFN2 highlights a critical and cryptic step for feedforward recruiting a pool of Parkin onto the mitochondrial surface,” says corresponding author Prof. Zee-Fen Chang.
“Without this lipid signal, PINK1-Parkin pathway is incomplete and unable to amplify the ubiquitination of mitochondrial outer membrane proteins required for degrading the dysfunctional mitochondria.”
Prof. Zee-Fen Chang's email address: zfchang@ntu.edu.tw
To see article on Asia Research News: https://www.asiaresearchnews.com/content/removing-dysfunctional-mitochondria-parkin-requires-lipid-signal