PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease

Abstract

Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis. Over the last decade, PINK1/Parkin-dependent mitochondrial quality control emerged as a pleiotropic regulatory pathway. Loss of its function impinges on a number of physiological processes suspected to contribute to PD pathogenesis. Its role in the regulation of innate immunity and inflammatory processes stands out, providing compelling support to the contribution of non-cell-autonomous immune mechanisms in PD. In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field.

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

“…The cooperation between PINK1 and Parkin in MQC mechanisms, ranging from the removal of damaged mitochondrial components to the degradation of whole dysfunctional organelles by mitophagy, has been studied in detail (McLelland et al, ; Mouton‐Liger, Jacoupy, Corvol, & Corti, ; Narendra et al, ; Pickrell & Youle, ). However, little is known about the impact of PINK1/Parkin‐dependent mitochondrial surveillance mechanisms and their dysfunction on the biology of the different cell types in the central nervous system, including glial cells in particular.…”

“…The cooperation between PINK1 and Parkin in MQC mechanisms, ranging from the removal of damaged mitochondrial components to the degradation of whole dysfunctional organelles by mitophagy, has been studied in detail (McLelland et al, 2014;Mouton-Liger, Jacoupy, Corvol, & Corti, 2017;Narendra et al, 2008;Pickrell & Youle, 2015).…”

Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

“…Parkin, together with PINK1, is critically important for mitochondrial quality control by modulating mitophagy, a form of autophagy which delivers damaged mitochondria to lysosomes for degradation. However, there is a large body of experimental evidence which extends the role of PRKN and PINK1 in mitochondrial quality control beyond the control of mitophagy 34 . Given that mitochondria are key players of adaptive and innate immunity, and the suggested role of Prkn and Pink in autoimmune-mediated neuronal destruction in a mouse model, it is possible that unrecognized infection provides the missing link between impaired mitochondrial quality control and dysregulated neuro-inflammation in EOPD 35 .…”

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

“…Furthermore, we demonstrate the mechanistic utility of this nematode model by identifying nicotine-activated neuroprotective signaling pathways functioning in DNs. Results of this analysis suggest involvement of the mitochondrial stress response, mitochondrial calcium accumulation, and PINK-1 [mutations in which are a cause of PD] in nicotine-mediated protection of DNs (Mouton-Liger, Jacoupy, Corvol, & Corti, 2017). The extensive axons, dense synapses, and high basal activity of substantia nigra DNs were suggested to increase metabolic load on these neurons, leading to their increased vulnerability to perturbations in mitochondrial function (Ge, Dawson, & Dawson, 2020).…”