Mutation of hop-1 and pink-1 attenuates vulnerability of neurotoxicity in C. elegans: the role of mitochondria-associated membrane proteins in Parkinsonism

Abstract

Mitochondrial dysfunction is considered as a critical mechanism in the pathogenesis of Parkinson's disease (PD). Increasing evidence supports the notion of mitochondria-associated membranes (MAMs) in mitochondrial dysfunction; yet little is known about the role of MAMs-related proteins in the pathogenesis of PD. Herein we exposed the nematode Caenorhabditis elegans to 0.5-10.0 μM rotenone (RO) or 0.2-1.6 mM paraquat (PQ) for 3 days. Our results showed that both RO and PQ induced similar Parkinsonism including motor deficits and dopaminergic degeneration. RO/PQ caused mitochondrial damages characterized by the increase of vacuole areas and autophagy vesicles, but the decrease of mitochondrial cristae. RO/PQ-impacted mitochondrial function was also demonstrated by the decrease of ATP level and mitochondrial membrane potential. Additionally, the attachment or surrounding of endoplasmic reticulum to the damaged mitochondria indicates ultrastructural alterations in MAMs. Using fluorescently labeled transgenic nematodes, we further found that the expression of tomm-7 and genes of Complex I, II and III was reduced, whereas the expression of pink-1 was increased in the exposed animals. To determine MAMs in toxicity toward PD, we investigated the mutants of hop-1 and pink-1, encoding presenilin and PTEN-induced putative kinase 1 (PINK1) in mitochondria-associated membranes, respectively. Results demonstrated that the mutation of both hop-1 and pink-1 reduced the vulnerability of lethal, behavioral, and mitochondrial toxicity induced by RO/PQ. These findings suggest that presenilin and PINK1 play important roles in the RO/PQ-induced neurotoxicity through the mechanisms involved in mitochondria-associated membranes.

Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration

“…For example, pdr-1 deficiency has been previously associated with increased sensitivity to manganese lethality [48], methyl mercury toxicity [49], and α-synuclein toxicities [47] but was protective against bacterial metabolite-induced dopaminergic neurodegeneration [37]. pink-1 deficiency protected against rotenone and paraquat toxicities [50] as well as bacterial metabolite-induced dopaminergic neurodegeneration [37] but sensitized against α-synuclein toxicities [47,51]. It should be noted that in most or all such studies, loss of pink-1 and pdr-1 led to basal dopaminergic neurodegeneration or other pathologies, such that “protection” could also be interpreted as a failure to exhibit additional stressor-induced dysfunction above that resulting from the background genetic deficiency.…”

Caffeine reduces deficits in mechanosensation and locomotion induced by L-DOPA and protects dopaminergic neurons in a transgenic Caenorhabditis elegans model of Parkinson’s disease

“…Further, since Ca 2þ influx to the cell is excessive when dopamine is overproduced, a danger arises regarding Ca 2þ overloading of the ER, which can lead to further mitochondrial dysfunction if the integrity of the TMCO1 channel is compromised by prior ROSinduced damage. Hence, it is possible that caffeine protects DAergic neurons by attenuating hop-1 or pink-1 expression and reducing intracellular ROS effects to preserve an ER TMCO1 channel ortholog in C. elegans, ultimately protecting the neurons in the presence of excessive dopamine (Wu et al 2018;Wang et al 2019). In contrast, we hypothesise that the lack of efficient caffeine delivery to the tail resulted in aberrant effects that may have been detrimental to the PDE neurons (Figure 3).…”

“…Hence, it is possible that caffeine protects DAergic neurons by attenuating hop-1 or pink-1 expression and reducing intracellular ROS effects to preserve an ER TMCO1 channel ortholog in C. elegans , ultimately protecting the neurons in the presence of excessive dopamine (Wu et al. 2018 ; Wang et al. 2019 ).…”

Infertility induced by auxin in PX627 Caenorhabditis elegans does not affect mitochondrial functions and aging parameters

“…To further strengthen these results we investigated the key genetic markers of longevity and stress-resistance, such as daf-16, aak-2 and sir-2.1 [23][24][25]. Up-regulation of daf-16 and sir-2.1 expression is well documented with longevity and improved stress resistance [26,27], especially after FUdR exposure [7].…”