ER-mitochondria signaling in Parkinson's disease

Abstract

Mitochondria form close physical contacts with a specialized domain of the endoplasmic reticulum (ER), known as the mitochondria-associated membrane (MAM). This association constitutes a key signaling hub to regulate several fundamental cellular processes. Alterations in ER-mitochondria signaling have pleiotropic effects on a variety of intracellular events resulting in mitochondrial damage, Ca²⁺ dyshomeostasis, ER stress and defects in lipid metabolism and autophagy. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases. Furthermore, increasing evidence highlights that ER-mitochondria signaling contributes to these diseases, including Parkinson's disease (PD). PD is the second most common neurodegenerative disorder, for which effective mechanism-based treatments remain elusive. Several PD-related proteins localize at mitochondria or MAM and have been shown to participate in ER-mitochondria signaling regulation. Likewise, PD-related mutations have been shown to damage this signaling. Could ER-mitochondria associations be the link between pathogenic mechanisms involved in PD, providing a common mechanism? Would this provide a pharmacological target for treating this devastating disease? In this review, we aim to summarize the current knowledge of ER-mitochondria signaling and the recent evidence concerning damage to this signaling in PD.

Fig. 1. Endoplasmic reticulum–mitochondria tethering complexes

Multiple structures that tether mitochondria with the mitochondria-associated membranes (MAMs) of endoplasmic reticulum (ER) have been described. Inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC1) interact via GRP75. Synaptojanin 2 binding protein (SYNJ2BP) interacts with the ribosome-binding protein 1 (RRBP1). The outer mitochondrial protein tyrosine phosphatase-interacting protein 51 (PTPIP51) interacts with vesicle-associated membrane proteins-associated protein B (VAPB) or oxysterol-binding protein-related proteins (ORP5/8) at the ER. B-cell receptor associated protein 31 (BAP31) binds to mitochondrial fission 1 protein (Fis1). ER-located mitofusin 2 (MFN2) interacts with mitochondrial MFN1/MFN2. Other proteins, such the ER sorting molecule phosphofurin acidic cluster sorting protein-2 (PACS-2), have been involved in ER–mitochondria association integrity. Yeasts specific proteins have also been described: the ER–mitochondria encounter structure (ERMES) complex, composed of four proteins: the outer mitochondrial membrane proteins Mdm10 and Mdm34, the ER protein Mmm1, and the cytosolic protein Mdm12

Fig. 2. Endoplasmic reticulum–mitochondria signaling function

The interaction between mitochondria and the MAMs of ER has been linked with different cellular functions, including inflammasome formation; calcium (Ca²⁺) signaling, mitochondrial and ER dynamics, autophagy and lipid biosynthesis. AMPK AMP-activated protein kinase, Casp-1 caspase-1, DRP1 dynamin-related protein 1, GRP75 glucose-regulated protein 75, IMM inner mitochondrial membrane, IP3R inositol 145-trisphosphate receptor, MCU mitochondrial calcium uniporter, MFN2 mitofusin 2, NLRP3 NLR family pyrin domain-containing 3, OMM outer mitochondrial membrane, PACS-2 phosphofurin acidic cluster sorting protein-2, PC phosphatidylcholine, PE phosphatidylethanolamine, PEMT2 phosphatidylethanolamine N-methyltransferase 2, PS phosphatidylserine, PSD phosphatidylserine decarboxylases, PTPIP51 protein tyrosine phosphatase-interacting protein 51, ROS radical oxygen species, TCA tricarboxylic acid cycle, UPR unfolded protein response, VAPB vesicle-associated membrane proteins-associated protein B, VDAC1 voltage-dependent anion channel 1

Fig. 3. Proposed model for endoplasmic reticulum–mitochondria signaling in PD

ER–mitochondrial axis appears to be essential for the healthy neurons. Conversely, the disruption of this interaction may involve the develop of some processes as: mitochondrial dysfunction, induction of oxidative stress, calcium (Ca²⁺) dyshomeostasis, autophagy defects or neuroinflammation, which induce neuronal damage and trigger neurodegenerative diseases as PD

Fig. 4. Modulators of ER–mitochondria associations

Several PD-associated proteins localize at the ER–mitochondrial (M) axis and have been shown to participate in ER–mitochondria signaling regulation. Proteins such as α-synuclein (α-syn), DJ-1, PINK1 (PTEN-induced putative kinase 1), or Parkin have an important role in the preservation of healthy cells by regulation of calcium (Ca²⁺) homeostasis and the autophagic responses under different stimulus (a). Dysfunction of these PD-associated proteins leads to a non-efficient interaction between ER and mitochondria that triggers cell damage (b). IP3R inositol 145-trisphosphate receptor, PTPIP51 protein tyrosine phosphatase-interacting protein 51, VAPB VAMP-associated protein B, VDAC1 voltage-dependent anion channel 1