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

Abstract

That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.

Keywords: Mitochondria; Mitophagy; PINK1; Parkin; Parkinson disease; Selective vulnerability; Substantia nigra.

Fig. 1

A model for the multifunctional role of PINK1/Parkin in mitochondrial quality control. Activation of PINK1/Parkin triggers multiple sequential and parallel mechanisms of a-c mitochondrial removal and d, e mitochondrial regeneration. Different mechanisms of mitochondrial removal are engaged depending on the severity of damage. a Mitochondria experiencing global/widespread damage undergo mitophagy, in which massive PINK1/Parkin activation recruits autophagosome membranes via Rab proteins and LC3 and is subsequently degraded by lysosomes, and b undergo mitochondrial fission caused by PINK1/Parkin dependent mitofusin degradation and Drp1 recruitment. c Focal damage leads to the activation of mitochondrial fission as well as mediate the Drp1-independent formation of MDVs, which allow for removal and destruction of small pockets of damaged mitochondrial components and limits the nonspecific destruction of functioning subdomains. d To replace the mitochondrial components removed through removal mechanisms, PINK1 phosphorylates PARIS and primes it for ubiquitination by Parkin. Subsequent proteosomal degradation of PARIS relieves PARIS-mediated transcriptional repression of PGC-1α, thereby stimulating mitochondrial biogenesis. e Furthermore, recent evidence suggests that PINK1/Parkin may promote local synthesis of nuclear-encoded mitochondrial proteins by bringing mRNAs encoding mitochondrial genes to the mitochondria and promoting translation initiation. f PINK1/Parkin activation further leads to the ubiquitination of TOM complex proteins Tom70 and Tom20, which promotes transport of newly synthesized proteins into the mitochondria, possibly as a means to facilitate the replacement of damaged protein degraded through other mechanisms

Fig. 2

Mechanisms of Parkin inactivation in sporadic PD. To date, the two most widely studied mechanisms by which Parkin is inactivated in sporadic PD is through chemical modifications leading to impaired enzyme activity (dopamine adducts, S-nitrosylation), and through α-synuclein aggregation. α-Synuclein aggregates lead to the activation of stress-induced kinases c-Abl and p38 MAPK, which phosphorylate and inactivate Parkin. These mechanisms therefore suggest that studies on the molecular mechanisms of neurodegeneration caused by complete Parkin loss (ie. Genetic knockout) may also be common mechanism of neurodegeneration between Parkin-induced PD and sporadic PD of unclear etiology. Some of these downstream pathways of neurodegeneration include (neuro)-immune overactivation, mitochondrial deficits, and the accumulation of Parkin substrates leading to activation of cell-death pathways