PINK1 cleavage at position A103 by the mitochondrial protease PARL

Abstract

Mutations in PTEN-induced kinase 1 (PINK1) cause early onset autosomal recessive Parkinson's disease (PD). PINK1 is a 63 kDa protein kinase, which exerts a neuroprotective function and is known to localize to mitochondria. Upon entry into the organelle, PINK1 is cleaved to produce a ∼53 kDa protein (ΔN-PINK1). In this paper, we show that PINK1 is cleaved between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1. We demonstrate that a reduced ability to cleave PINK1, and the consequent accumulation of full-length protein, results in mitochondrial abnormalities reminiscent of those observed in PINK1 knockout cells, including disruption of the mitochondrial network and a reduction in mitochondrial mass. Notably, we assessed three N-terminal PD-associated PINK1 mutations located close to the cleavage site and, while these do not prevent PINK1 cleavage, they alter the ratio of full-length to ΔN-PINK1 protein in cells, resulting in an altered mitochondrial phenotype. Finally, we show that PINK1 interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and that loss of PARL results in aberrant PINK1 cleavage in mammalian cells. These combined results suggest that PINK1 cleavage is important for basal mitochondrial health and that PARL cleaves PINK1 to produce the ΔN-PINK1 fragment.

The pathways of mitophagy for quality control and clearance of mitochondria

“…48 In healthy mitochondria, PINK1 is constitutively imported, probably via the TIM/TOM complex, to the inner membrane where it is cleaved by several proteases including the mitochondrial-processing protease (MPP) and the inner membrane presenilin-associated rhomboid-like protease PARL, and ultimately proteolytically degraded ( Figure 4A). [70][71][72][73] Loss of mitochondrial membrane potential may be the event that acutely activates this pathway; loss of the potential gradient precludes import of PINK1 to the inner membrane, thereby stabilizing intact PINK1 on the mitochondrial outer membrane where it interacts with the TOM complex. 74 In this manner, PINK1 serves as a sensor for mitochondrial damage.…”

Quality Control of Mitochondrial Proteostasis

“…Although the precise role of Pink1 is unclear, recent work has shown that under physiological conditions Pink1 is imported into mitochondria and cleaved by the mitochondrial IM rhomboid protease PARL (Fig. 5B) (Deas et al 2010;Jin et al 2010). Following its cleavage, Pink1 is constitutively turned over by an as yet unknown protease that is sensitive to MG132.…”

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…Subsequent studies suggested that mitochondrial depolarization inhibits PINK1 protein degradation induced by mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and promotes the accumulation of full-length PINK1 in the mitochondrial outer membrane to recruit Parkin (Jin et al, 2010). However, other researchers argue that the mitochondrial proteasemediated processing of PINK1 is critical for its mitochondrial protective function (Deas et al, 2011;Shi et al, 2011). Therefore, further investigation is needed to fully understand the molecular activation mechanism of PINK1 in mitochondrial protection as well as the roles of both the full-length and cleaved forms of PINK1 in vivo.…”