PINK 1 phosphorylates Drp1 ^S616 to regulate mitophagy‐independent mitochondrial dynamics

Abstract

Impairment of PINK1/parkin-mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD). We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. Drp1 S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, but unaffected by parkin inactivation. PINK1-mediated mitochondrial fission is Drp1 S616 phosphorylation dependent. Overexpression of either wild-type Drp1 or of the phosphomimetic mutant Drp1 S616D , but not a dephosphorylation-mimic mutant Drp1 S616A , rescues PINK1 deficiency-associated phenotypes in Drosophila. Moreover, Drp1 restores PINK1-dependent mitochondrial fission in ATG5-null cells and ATG7-null Drosophila. Reduced Drp1 S616 phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK1 and a novel mechanism how PINK1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK1-mediated Drp1 S616 phosphorylation with the pathogenesis of both familial and sporadic PD.

Autophagy and the endolysosomal system in presynaptic function

“…Selective removal of these organelles by autophagy, a process termed mitophagy, has been shown to occur at distal axons [59] and mitochondria are commonly found in autophagosomes [60]. Likewise, the molecular mechanisms of mitophagy are well-studied [61,62] and mutations in the key mitophagy adaptors, PINK1 and Parkin, are linked to early onset familiar Parkinson's Disease [63]. Another organelle tightly linked to autophagy is the ER, a continuous network of tubuli that extends throughout the neuronal cytoplasm and that participates in the synthesis of essential cellular components such as membrane, lipids and transmembrane proteins as well as calcium storage.…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…This process is mediated by the phosphorylation of Drp1 by GSK3b (which is activated by ROS) [ 189 ], and also by phosphorylation of MFF, a receptor of DRP1, by AMPK (which is also activated by ROS) [ 140 , 145 , 146 ]. Additionally, PINK1, which is recruited to the mitochondria by the collapse of ∆Ѱ, also phosphorylates Drp1 [ 194 ]. The combination of enhanced mROS and ∆Ѱ collapse is indicative of mPTP activation, and there is direct evidence that mPTP enhances mitochondrial fission [ 195 ].…”

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

“…In dopaminergic mouse neuronal cells (SN4741), DRP1 Ser616 is phosphorylated by p38 MAPK, which increases its mitochondrial translocation, resulting in mitochondrial dysfunction and neuronal loss [ 51 ]. The phosphorylation of DRP1 associated with mitophagy inhibition is abolished by the activity of PTEN -induced putative kinase 1 (PINK1) [ 52 ]. PINK1, when targeted into the mitochondria, disrupts the anchoring of PKA to the OMM by inhibiting its binding to AKAP1 and thus ensuring the necessary fission of damaged mitochondria for organellar degradation [ 53 ].…”