Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control

Abstract

Mitochondria, which convert energy for the cell, accumulate damage with age, and the resulting mitochondrial dysfunction has been linked to the development of degenerative diseases and aging. To curb the accumulation of damaged mitochondria, the cell has elaborated a number of mitochondrial quality control processes. We describe recent work suggesting that Parkin and PTEN-induced putative kinase 1 (PINK1), two gene products linked to familial forms of parkinsonism, may constitute one of the cell's mitochondrial quality control pathways-identifying impaired mitochondria and selectively trimming them from the mitochondrial network by mitophagy. In particular, we discuss the regulation of PINK1 protein expression and Parkin localization by the bioenergetic status of individual mitochondria; the mechanism by which PINK1 recruits Parkin to the outer mitochondrial membrane; and Parkin's promotion of mitophagy through its ubiquitination of outer mitochondrial membrane proteins. This recent work suggests that Parkin and PINK1 may be among the first mammalian proteins identified with a direct role in regulating mitophagy, and implicate a failure of mitophagy in the pathogenesis of Parkinson's disease.

FIG. 1.

Schematic depicting ion transport across the inner mitochondrial membrane. Parkin is recruited to mitochondria with low voltage (ΔΨ) across the inner mitochondrial membrane. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Cartoon depicting regulation of PINK1 processing by voltage potential across the inner mitochondrial membrane. PTEN-induced putative kinase 1 (PINK1) is proteolytically cleaved and degraded in healthy mitochondria but stabilized on mitochondria with low inner membrane voltage (ΔΨ). (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

Several models for the recruitment of Parkin to mitochondria by the kinase PINK1. In the direct binding model, PINK1 recruits Parkin through direct binding. In the direct phosphorylation model, phosphorylation of Parkin by PINK1 increases Parkin's affinity for depolarized mitochondria. In the shared substrate model, PINK1's phosphorylation of mitochondrial proteins increases their affinity for the E3 ubiquitin ligase Parkin. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

PINK1 and Parkin target depolarized mitochondria for autophagic degradation. PINK1 selectively accumulates on mitochondria with low voltage (ΔΨ) across their inner membranes. The accumulated PINK1 directs Parkin to mitochondria with low ΔΨ. Parkin tags the dysfunctional mitochondria with ubiquitin, which likely serves as the signal for their subsequent degradation in lysosomes. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5.

Cartoon depicting substrates ubiquitinated by Parkin and ubiquitin-binding adapter proteins recruited by Parkin. Ubiquitination of mitochondrial membrane proteins by Parkin results in mitochondrial quality control likely mediated by different ubiquitin-binding adaptor proteins. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).