Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson's Disease

Abstract

Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson's disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited. PINK1 is proteolytically processed in the intermembrane space and matrix of the mitochondria into functional cleaved products (c-PINK1) that are exported to the cytosol. While it is clear that posttranslational processing of PINK1 depends on the mitochondria's oxidative state and structural integrity, the functional roles of c-PINK1 in modulating neuronal functions are poorly understood. Here, we review the diverse roles played by c-PINK1 in modulating various neuronal functions. Specifically, we describe the non-canonical functional roles of PINK1, including but not limited to: governing mitochondrial movement, neuronal development, neuronal survival, and neurogenesis. We have published that c-PINK1 stimulates neuronal plasticity and differentiation via the PINK1-PKA-BDNF signaling cascade. In addition, we provide insight into how mitochondrial membrane potential-dependent processing of PINK1 confers conditional retrograde signaling functions to PINK1. Further studies delineating the role of c-PINK1 in neurons would increase our understanding regarding the role played by PINK1 in PD pathogenesis.

Keywords: BDNF (brain derived neurotrophic factor); PKA signaling; Parkinson’s disease; cleaved PINK1; mitochondrial retrograde signaling; neuronal plasticity and neurogenesis.

FIGURE 1

Proteolytic processing of PINK1. PINK1 gene encodes a 581 amino acid protein with an N-terminal mitochondrial targeting motif that contains a transmembrane domain (110 amino acids long), an un-conserved region, a kinase domain with three insertions in the N lobe, and a conserved C-terminal region (CTR). IMM-localized mitochondrial processing peptidases (MPP) putatively cleave PINK1 at aa 34 and 35 to form a 60 kDa intermediate cleavage product. PARL and/or m-AAA cleave the intermediate 60 kDa intermediate product in between Ala103 and Phe104 to generate 52/48 kDa processed forms of PINK1.

FIGURE 2

Schematic of the canonical role of PINK1 in mitophagy: Upon loss of ΔΨm the import of PINK1 into the IMM is blocked which results in the overt accumulation of PINK1 at the OMM, which blocks mitochondrial import of mitochondrially-localized proteins mediated by the TOM complex. At the OMM, PINK1 can autophosphorylate itself, phosphorylate ubiquitin and Parkin in order to recruit and activate Parkin at the damaged mitochondria. Parkin ubiquitinates several mitochondrial substrates such as Mfn, VDAC1 and Drp1. Poly-Ub chains are subsequently phosphorylated by PINK1 serving as a signal for the autophagic machinery to trigger the initiation of mitophagy. Adaptor proteins (OPTN, NDP52) recognize phosphorylated poly-Ub chains on mitochondrial proteins and initiate autophagosome formation through binding with LC3.

FIGURE 3

Schematic of the non-canonical role of c-PINK1 in neuronal function. Conditional proteolytic processing: In healthy neurons, most mitochondria are highly functional, as evident by an adequate ΔΨm that enables the import of PINK1 via the TOM-TIM protein import complex at the OMM and IMM, respectively. In healthy mitochondria, PINK1 is cleaved by PARL and MPP at the IMM, and the cleaved PINK1 (c-PINK1) is retro-translocated to the cytosol to exert extra-mitochondrial functions. PINK1-PKA-CREB-BDNF signaling; Mitochondria with optimum ΔΨm proteolytically processes f-PINK1 to c-PINK1. The c-PINK1 stabilizes and retro-translocated to the cytosol and phosphorylates the catalytic subunit of PKA and enhances PKA mediated CREB activation, resulting in upregulated BDNF expression and release. BDNF, a neurotrophic factor augments neuronal plasticity. c-PINK1 degradation through N-end rule pathway: The N-end rule specific E3 enzymes UBR1, UBR2, and UBR4 recognize the N-terminal phenylalanine residue of c- PINK1 for proteasomal degradation. AKT activation: Activation of PINK1 leads to phosphorylation of cytosol localized AKT. Mitochondrial movement: f-PINK1 phosphorylates Miro1 to arrest mitochondrial movement. However, c-PINK1 can activate PKA-mediated phosphorylation of Miro2 to enhance the anterograde movement of mitochondria in dendrites and axons. Anti-apoptotic: PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein, hindering the pro-apoptotic cleavage of Bcl-xL. Degradation of misfolded proteins: Parkin, PINK1, and DJ-1 form a PPD complex to promote ubiquitination and degradation of Parkin substrates and PINK1 mutation leads to decreased degradation and accumulation of abnormally folded Parkin substrates.