PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

Abstract

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

Inflammasome and Mitophagy Connection in Health and Disease

“…PINK1/Parkin-dependent mitophagy is a well-known post-translational signaling cascade that recognizes the cargo through the polyubiquitination of mitochondrial proteins and the recruitment of the autophagic machinery [ 88 , 89 ] ( Figure 2 ). Mitochondrial Ser/Thr kinase PINK1 level is very low through constitutive degradation in physiological condition [ 90 ]. Once ΔΨ M is dissipated, translocase of the inner membrane (TIM)23-mediated import of PINK1 is inhibited, thus being accumulated on the outer membrane (OMM) [ 90 ].…”

“…Mitochondrial Ser/Thr kinase PINK1 level is very low through constitutive degradation in physiological condition [ 90 ]. Once ΔΨ M is dissipated, translocase of the inner membrane (TIM)23-mediated import of PINK1 is inhibited, thus being accumulated on the outer membrane (OMM) [ 90 ]. A supercomplex containing PINK1 homodimers facilitates PINK1 activation to phosphorylate the ubiquitinated substrates on the OMM [ 90 ].…”

“…Once ΔΨ M is dissipated, translocase of the inner membrane (TIM)23-mediated import of PINK1 is inhibited, thus being accumulated on the outer membrane (OMM) [ 90 ]. A supercomplex containing PINK1 homodimers facilitates PINK1 activation to phosphorylate the ubiquitinated substrates on the OMM [ 90 ]. In addition, the activated PINK1 recruits and phosphorylates Parkin, the E3 ubiquitin ligase [ 89 , 91 ].…”

The Links between Parkinson’s Disease and Cancer

“…Mutations in LRRK2 and the genes coding α-synuclein cause autosomal dominant hereditary PD, whereas mutations in DJ-1, PARKIN, PINK1, and ATP13A2 cause autosomal recessive variants. Many of these proteins are involved in mitochondrial or lysosomal functioning [ 5 ], and patients with PD present mitochondrial deficits and autophagy pathway impairment. These data suggest a possible role of mitochondrial and lysosomal dysfunction in PD’s pathogenesis.…”

G protein-coupled receptor signaling regulates ER-mitochondria contacts

“…Accumulating evidences indicate that ER-Mito contact dysfunction contributes to a variety of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis with associated fronto-temporal dementia (ALS/FTD), Charcot-Marie-Tooth (CMT) disease and hereditary spastic paraplegia (HSP)(19,20,77,78). For example, disease-associated mutations in presenilin1 and 2 in AD(25,26,79,80); a-synuclein (a-syn), DJ-1, PINK1 and parkin in PD(81)(82)(83)(84)(85)(86); FUS, TDP43, SOD1 in ALS/FTD(32,33); Mitofusin 2 in CMT(14); and REEP1 in HSP(23), have all shown to alter ER-Mito contacts, with evidence suggesting this change contributes to the neurodegeneration.…”