Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10

Abstract

Mutations of the PARK2 and PINK1 genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/ threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas PARK2 downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with PARK2 mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing PARK2 mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fissionpromiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated HSD17B10 silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD. Parkinson's disease (PD) is the most common neurodegenerative movement disorder. It is caused by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta. It is mostly sporadic, but about 10% of cases are familial forms with Mendelian inheritance.1 Autosomal recessive forms of PD are caused by mutations of PARK2/parkin, PINK1, DJ-1 and ATP13A2. PARK2 mutations are responsible for almost 40% of cases beginning before the age of 45. Parkin is a cytosolic RING-in-between-RING ubiquitin ligase with HECT-like enzyme activity; 2 it has versatile ubiquitylation activities and various putative protein substrates with diverse functions, involved in different cellular processes.1 Genetic studies in Drosophila have shown Parkin and the mitochondrial serine/threonine kinase PINK1 to be components of a molecular pathway maintaining mitochondrial physiology. [3][4][5][6][7] In mammalian cells, PINK1 and Parkin cooperate in the clearance of dysfunctional mitochondria. The disruption of mitochondrial membrane (MM) potential (ΔΨm) by uncouplers or oxidative stress leads to PINK1 accumulation on the outer MM (OMM), the PINK1-dependent recruitment ...

LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease

“…1D). As expected from our previous experience (36)(37)(38), the proportion of cells with mitochondrial aggregates progressively increased in the presence of overexpressed Parkin, reaching a plateau after 8 h of CCCP treatment. A similar progression was observed in cells coexpressing the kinase-dead LRRK2-D1994A variant.…”

“…We investigated the possible role of LRRK2 in PINK1/Parkin-dependent mitophagy in a model previously validated for the investigation of this process (36)(37)(38). In this model, Parkin is transiently overexpressed in COS7 cells.…”

PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

“…Several proteomics profiling and biochemical studies in Drosophila and human cells have found that PINK1-activated Parkin can induce ubiquitylation of TOM receptor proteins Tom70 and Tom20 [63,72,167,168]. This ubiquitylation may increase the import of the endogenous mitochondrial protein HSD17B10 or a reporter peptide carrying a MTS, with cells carrying PD-associated PINK1 or PRKN showing impaired import [168,169]. If these findings generalize to other imported proteins, it would suggest that PINK1/Parkin may also directly drive protein influx into the mitochondria through posttranslational regulation of the TOM complex.…”

Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases

“…Nearly 40% of the Parkinson's disease cases beginning before age 45 are due to PARK2 mutations. These mutations prevent ubiquitylation of HSD10, leading to reduced import into the mitochondria (Bertolin et al 2015). Disruption of HSD10 import would effectively remove its ability to deplete CL ox levels and could lead to rampant apoptosis (Fig.…”

“…HSD10 is imported into the mitochondria by a pathway involving Parkin, a protein whose function is abrogated in patients with Parkinson's disease (Bertolin et al 2015). A wide variety of enzymatic activities have been associated with HSD10 (Yang et al 2014), and their clinical significance has been examined extensively.…”