Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson’s Disease: The Role of Brain Renin Angiotensin System Components

Tuladhar, Sunanda; Ray, Bipul; Mahalakshmi, Arehally M.; Bhat, Abid; Rashan, Luay; Rungratanawanich, Wiramon; Song, Byoung Joon; Essa, Musthafa Mohamed; Sakharkar, Meena Kishore; Chidambaram, Saravana Babu

doi:10.3390/biom11111669

Cited by 22 publications

(15 citation statements)

References 168 publications

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“…This connection may be related to the communication between ER and mitochondria. Recent studies have shown that mitochondria form close physical contacts with a specialized domain of the ER, known as the mitochondria-associated membrane (MAM) [ 43 ], and this association constitutes a key signaling hub to regulate a plethora of fundamental cellular processes, such as Ca 2+ homeostasis, lipid synthesis and mitophagy [ 43 , 44 , 45 ]. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases and increasing evidence highlights that alterations in ER-mitochondria signaling contribute to these diseases, including PD.…”

Section: Discussionmentioning

confidence: 99%

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

Liao

Gong

Wang

et al. 2022

Cells

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Neuronal oxidative stress caused by mitochondrial dysfunction plays a crucial role in the development of Parkinson’s disease (PD). Growing evidence shows that autophagy confers neuroprotection in oxidative-stress-associated PD. This work aims to investigate the involvement of TMEM166, an endoplasmic-reticulum-localized autophagy-regulating protein, in the process of PD-associated oxidative stress through the classic cellular PD model of neuroblastoma SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+). Reactive oxygen species (ROS) production and mitochondrial membrane potential were checked to assess the oxidative stress induced by MPP+ and the cellular ATP generated was determined to evaluate mitochondrial function. The effect on autophagy induction was evaluated by analyzing p62 and LC3-II/I expression and by observing the LC3 puncta and the colocalization of LC3 with LAMP1/ LAMP2. The colocalization of mitochondria with LC3, the colocalization of Tom20 with LAMP1 and Tom20 expression were analyzed to evaluate mitophagy. We found that TMEM166 is up-regulated in transcript levels, but up-regulated first and then down-regulated by autophagic degradation in protein levels upon MPP+-treatment. Overexpression of TMEM166 induces mitochondria fragmentation and dysfunction and exacerbates MPP+-induced oxidative stress and cell viability reduction. Overexpression of TMEM166 is sufficient to induce autophagy and mitophagy and promotes autophagy and mitophagy under MPP+ treatment, while knockdown of TMEM166 inhibits basal autophagic degradation. In addition, overexpressed TMEM166 suppresses AMPK activation, while TMEM166 knockdown enhances AMPK activation. Pharmacological activation of AMPK alleviates the exacerbation of oxidative stress induced by TMEM166 overexpression and increases cell viability, while pharmacological inhibition mitophagy aggravates the oxidative stress induced by MPP+ treatment combined with TMEM166 overexpression. Finally, we find that overexpressed TMEM166 partially localizes to mitochondria and, simultaneously, the active AMPK in mitochondria is decreased. Collectively, these findings suggest that TMEM166 can translocate from ER to mitochondria and inhibit AMPK activation and, in response to mitochondrial oxidative stress, neuronal cells choose to up-regulate TMEM166 to promote autophagy/mitophagy; then, the enhancing autophagy/mitophagy degrades the TMEM166 to activate AMPK, by the two means to maintain cell survival. The continuous synthesis and degradation of TMEM166 in autophagy/mitochondria flux suggest that TMEM166 may act as an autophagy/mitochondria adaptor.

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Section: Discussionmentioning

confidence: 99%

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

Liao

Gong

Wang

et al. 2022

Cells

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“…ROS facilitates plasma membrane Ca 2+ -permeable channels and organelle membrane Ca 2+ release channels, however, it inhibits Ca 2+ -ATPase and Ca 2+ -transporters, which are responsible for pumping Ca 2+ out of the cell or uptake by organelles, respectively ( Görlach et al, 2015 ). Recently, accumulating evidence has shown that Ca 2+ dyshomeostasis, ER stress, mitochondrial oxidative stress, and impaired autophagy typically appear in SNc DA neurons in PD ( Abou-Sleiman et al, 2006 ; Calì et al, 2011 ; Michel et al, 2016 ; Sunanda et al, 2021 ), suggesting that dyshomeostasis is likely a common pathway in PD pathogenesis.…”

Section: Ca 2+ Dyshomeostasis Mediates the Vicious...mentioning

confidence: 99%

“…Although a number of PD risk factors have been identified, the molecular pathways of risk factor-related progressive neurodegeneration in PD require further elucidation. Dysfunction of the endoplasmic reticulum (ER), mitochondria, and lysosomes has been proposed to be the primary cause of neuronal death in PD patients ( Michel et al, 2016 ; Sunanda et al, 2021 ). Dysfunction of the ER causes accumulation of unfolded proteins, which in turn triggers ER stress, resulting in an unfolded protein response (UPR).…”

Section: Introductionmentioning

confidence: 99%

Ca2+ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson’s Disease

Minobe

Kameyama

2022

Front. Cell. Neurosci.

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Parkinson’s disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although the precise causes of PD are still unknown, several risk factors for PD have been determined, including aging, genetic mutations, environmental factors, and gender. Currently, the molecular mechanisms underlying risk factor-related neurodegeneration in PD remain elusive. Endoplasmic reticulum stress, excessive reactive oxygen species production, and impaired autophagy have been implicated in neuronal death in the SNc in PD. Considering that these pathological processes are tightly associated with intracellular Ca2+, it is reasonable to hypothesize that dysregulation of Ca2+ handling may mediate risk factors-related PD pathogenesis. We review the recent findings on how risk factors cause Ca2+ dyshomeostasis and how aberrant Ca2+ handling triggers dopaminergic neurodegeneration in the SNc in PD, thus putting forward the possibility that manipulation of specific Ca2+ handling proteins and subcellular Ca2+ homeostasis may lead to new promising strategies for PD treatment.

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“…The mechanisms were hypothesized that resveratrol modulated the pAMPK/AMPK pathway to stimulate the Ca 2+ level [77]. The pathogenic mutation in α-Syn, one kind of PD-related gene, leads to pathological changes in MAMs, decreases its association, and disrupts autophagy [78][79][80][81]. In addition, PINK1induced alterations in MAMs have been observed in renal ischemia-reperfusion (I/R) [82].…”

Section: Mams Positively Regulate Autophagymentioning

confidence: 99%

Mitochondria-Associated Endoplasmic Reticulum Membranes: Inextricably Linked with Autophagy Process

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Mitochondria-associated membranes (MAMs), physical connection sites between the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM), are involved in numerous cellular processes, such as calcium ion transport, lipid metabolism, autophagy, ER stress, mitochondria morphology, and apoptosis. Autophagy is a highly conserved intracellular process in which cellular contents are delivered by double-membrane vesicles, called autophagosomes, to the lysosomes for destruction and recycling. Autophagy, typically triggered by stress, eliminates damaged or redundant protein molecules and organelles to maintain regular cellular activity. Dysfunction of MAMs or autophagy is intimately associated with various diseases, including aging, cardiovascular, infections, cancer, multiple toxic agents, and some genetic disorders. Increasing evidence has shown that MAMs play a significant role in autophagy development and maturation. In our study, we concentrated on two opposing functions of MAMs in autophagy: facilitating the formation of autophagosomes and inhibiting autophagy. We recognized the link between MAMs and autophagy in the occurrence and progression of the diseases and therefore collated and summarized the existing intrinsic molecular mechanisms. Furthermore, we draw attention to several crucial data and open issues in the area that may be helpful for further study.

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Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson’s Disease: The Role of Brain Renin Angiotensin System Components

Cited by 22 publications

References 168 publications

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

Ca2+ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson’s Disease

Mitochondria-Associated Endoplasmic Reticulum Membranes: Inextricably Linked with Autophagy Process

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