Removing dysfunctional mitochondria by Parkin requires a lipid signal
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's disease, PINK1 and Parkin have been identified as the causative genes. The accumulation of dysfunctional mitochondria is toxic to neurons. 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.
A study published in Autophagy, uncovers 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 the mitochondrial outer membrane. NME3 deficiency is associated with neurodegenerative disorder in a fatal newborn.
The mechanistic investigation reveals that NME3 cooperates with mitoPLD to convert cardiolipin, a unique mitochondrial lipid, to phosphatidic acid on the 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 the 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 Zee-Fen Chang, chair professor of molecular medicine at National Taiwan University.
"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."
More information:
Chih-Wei Chen et al, PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering, Autophagy (2026). DOI: 10.1080/15548627.2026.2623981
Provided by National Taiwan University
