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.

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

“…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). Thus, our findings showing nicotine-induced activation of the PINK-1 mitochondrial quality control pathway may explain selective protection afforded by tobacco smoking to these neurons.…”

“…Lastly, we examined the interaction of nicotine with PINK-1, a kinase which is stimulated by mitochondrial stress to activate mitophagy and additional protective processes mostly involving mitochondrial quality control (Ge et al, 2020;Mouton-Liger et al, 2017). RNAi silencing of pink-1, without nicotine, does not enhance dopaminergic neurodegeneration when compared to the EV control but it has been shown to do so in presence of other neuronal stressors, such as -synuclein overexpression in DNs (Martinez et al, 2015).…”

The Links between Parkinson’s Disease and Cancer

“…Having many functions, they are structures susceptible to damage [ 165 ]. An increased number of dysfunctional mitochondria may participate in the pathogenesis of many diseases including cancer, diabetes, anemia, and neurological disorders—acute (e.g., ischemic stroke and mechanical trauma) as well as chronic neurodegeneration (e.g., Alzheimer’s disease, PD, Huntington’s disease, or amyotrophic lateral sclerosis) [ 166 , 167 , 168 ]. The malfunction of mitochondria is mainly manifested in an energy failure of the affected tissue, a decrease in the activity of electron transport chain complexes, the overproduction of free radicals, disorders of cellular Ca 2+ ion homeostasis, the release of pro-apoptotic factors, and disorders of mitochondrial biogenesis.…”

Effects on Dopaminergic Neurons Are Secondary in COX-Deficient Locomotor Dysfunction in Drosophila

“…Mitochondrial stress, whether resulting from impaired respiration, oxidative damage, or defective protein quality control, has been proposed as a major underlying process in neurological diseases, notably those where locomotion is impaired, such as Parkinson's disease (PD; recently reviewed by Ge et al., 2020 ). The main pathological target in such diseases is dopaminergic (DA) neurons ( Lees et al., 2009 ), and these are believed to be specifically sensitive to mitochondrial dysfunction ( Bose and Beal, 2016 ), whether induced by toxins ( Terron et al., 2018 ), genetic predisposition ( Deng et al., 2018 ), or somatic accumulation of genetic damage, such as to mitochondrial DNA ( Bender et al., 2006 ; Kraytsberg et al., 2006 ).…”