PINK1 import regulation at a crossroad of mitochondrial fate: the molecular mechanisms of PINK1 import


PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase whose activity is tightly regulated by the mitochondrial health status. In response to mitochondrial damage, activated PINK1 can promote mitophagy, an autophagic elimination of damaged mitochondria, by cooperating with Parkin ubiquitin ligase. Loss-of-function of PINK1/Parkin-mediated mitophagy results in the accumulation of dysfunctional mitochondria, which could be one aetiology of Parkinson’s disease (PD). Within step-by-step signalling cascades of PINK1/Parkin-mediated mitophagy, mitochondrial damage-dependent PINK1 kinase activation is a critical step to trigger the mitophagy signal. Recent investigation of this process reveals that this stress-dependent PINK1 kinase activation is achieved by its regulated import into different mitochondrial compartments. Thus, PINK1 import regulation stands at an important crossroad to determine the mitochondrial fate—‘keep’ or ‘remove’? In this review, we will summarize how the PINK1 import is regulated in a mitochondrial health status-dependent manner and how this process could be pharmacologically modulated to activate the PINK1/Parkin pathway.

PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy is one of the stress-responsive signalling pathways of mitochondria, which can eliminate damaged, dysfunctional mitochondria from cells by autophagy. Both PINK1, a mitochondrial Ser/Thr kinase, and Parkin, a cytosolic RING-between-RING-type E3 ubiquitin ligase, were identified as autosomal recessive genes for familial recessive early-onset Parkinson’s disease (PD), suggesting that an impairment of mitophagy may be one aetiology of the disease. Accumulating evidence from the last 10 years suggests that PINK1/Parkin-mediated mitophagy is initiated by PINK1 kinase activation. Under steady-state conditions, the enzymatic activity of PINK1 is kept in an inactive state, but once mitochondria are damaged, it becomes active specifically on damaged mitochondria. The activated PINK1 phosphorylates ubiquitin molecules on the mitochondrial surface, which recruits cytosolic Parkin to damaged mitochondria (7, 8). The E3 ligase activity of Parkin is activated by binding to phospho-ubiquitin, and its active state is stabilized by PINK1-mediated phosphorylation of Parkin’s ubiquitin-like domain. Activated Parkin ubiquitinates several mitochondrial proteins, which are further phosphorylated by the activated PINK1, leading to the enrichment of the phosphorylated ubiquitin-chains on the surface of damaged mitochondria. This positive feedback amplification cycle created by PINK1 and Parkin through phospho-ubiquitin finally activates several autophagic machineries to engulf damaged mitochondria.

In addition to PINK1, it has been reported that the activity of other mitochondrial proteins is regulated by the interplay between mitochondrial import machineries and proteases. For example, ATFS-1 is a unique transcription factor in Caenorhabditis elegans that has both a mitochondrial and a nuclear import signal in one protein. Under steady-state conditions, it is constitutively degraded by LON protease after mitochondrial import. In contrast, it can function as a transcription factor in the nucleus when mitochondrial unfolded proteins are accumulated. It is intriguing that PINK1 import arrest and subsequent Parkin recruitment is also induced by the accumulation of mitochondrial aggregates (in this case, mitochondrial depolarization does not accompany with). These findings indicate that mitochondrial import machinery is not just an entry gate of proteins into mitochondria, and mitochondrial protease is not just a degrading-machinery of unfolded proteins. They can convey information from mitochondria to the cytosol through their client proteins, and be actively involved in stress signalling pathways in mitochondria. The detailed analysis of the regulation of mitochondrial import machineries and proteases will provide novel insights regarding how mitochondria sense their damage. Also, the stress sensitivity of mitochondrial could be pharmacologically modulated by targeting these molecular machineries, which will bring us to a new direction of drug discovery

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Journal of Biomolecules and Biochemistry
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