Targeting mitochondrial calcium pathways as a potential treatment against Parkinson’s disease

Dey, Kuntal; Bazała, M.; Kuźnicki, Jacek

doi:10.1016/j.ceca.2020.102216

Cited by 31 publications

(23 citation statements)

References 111 publications

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“…Also, increased intracellular Ca 2+ levels alter Ca 2+ handling in intracellular organelles such as the endoplasmic reticulum and mitochondria which may potentiate pathological effects [64]. Indeed, Ca 2+ uptake into the mitochondria is a key mechanism by which cells maintain intracellular Ca 2+ homeostasis [101,102]. However, excessive mitochondrial Ca 2+ uptake or impaired Ca 2+ e ux results in ROS production [103,104] and disruption of membrane potential inducing neuronal cell death, an important indicator of several different neurological disorders including Alzheimer's Disease (AD) and PD.…”

Section: Discussionmentioning

confidence: 99%

Commensal Gut Bacterium Akkermansia Muciniphila Secretome Induces Mitochondrial Calcium Overload and α-Synuclein Aggregation in Enteroendocrine Cells

Neto¹,

Bosque²,

Godoy³

et al. 2021

Preprint

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Background: The notion that the gut microbiota plays a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A. muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila conditioned medium could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. Results: We found that A. muciniphila conditioned medium is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. Indeed, oral administration of A. muciniphila cultivated in the absence of mucin to aged mice also led to αSyn aggregation in cholecystokinin (CCK)-positive enteroendocrine cells. Noteworthy, buffering mitochondrial Ca2+ reverted all the damaging effects observed. Conclusion: Thereby, these molecular insights provided here offer evidence that bacterial proteins are capable of inducing αSyn aggregation in enteroendocrine cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Commensal Gut Bacterium Akkermansia Muciniphila Secretome Induces Mitochondrial Calcium Overload and α-Synuclein Aggregation in Enteroendocrine Cells

Neto¹,

Bosque²,

Godoy³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, DAergic neurons derived from induced pluripotent stem cells from familial PD patients are protected from rotenone toxicity upon Cav3 channel inhibition [ 401 ], while knock-out of Cav2.3 channels protects mice from MPTP neurotoxicity [ 99 ]. Negative modulators of the MCUC [ 402 ] could decrease mitochondrial oxidant stress. Agonists of lysosomal Ca 2+ channels could enhance lysosomal exocytosis and diminish αSYN accumulation [ 403 ].…”

Section: Discussionmentioning

confidence: 99%

Calcium, Bioenergetics, and Parkinson’s Disease

Zampese

Surmeier

2020

Cells

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Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson’s disease (PD). These neurons are autonomous pacemakers that have large cytosolic Ca2+ oscillations that have been linked to basal mitochondrial oxidant stress and turnover. This review explores the origin of Ca2+ oscillations and their role in the control of mitochondrial respiration, bioenergetics, and mitochondrial oxidant stress.

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“…Also, increased intracellular Ca 2+ levels alter Ca 2+ handling in intracellular organelles such as the endoplasmic reticulum and mitochondria which may potentiate pathological effects (Ludtmann & Abramov, 2018). Indeed, Ca 2+ uptake into the mitochondria is a key mechanism by which cells maintain intracellular Ca 2+ homeostasis (Dey et al, 2020; Vos et al, 2010). However, excessive mitochondrial Ca 2+ uptake or impaired Ca 2+ efflux results in ROS production (Luongo et al, 2017; Reynolds & Hastings, 1995) and disruption of membrane potential inducing neuronal cell death, an important indicator of several different neurological disorders including Alzheimer’s Disease (AD) and PD.…”

Section: Discussionmentioning

confidence: 99%

Akkermansia muciniphilasecretome promotes α-synuclein aggregation in enteroendocrine cells

Jvp

et al. 2021

Preprint

View full text Add to dashboard Cite

The notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson's disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.

show abstract

Targeting mitochondrial calcium pathways as a potential treatment against Parkinson’s disease

Cited by 31 publications

References 111 publications

Commensal Gut Bacterium Akkermansia Muciniphila Secretome Induces Mitochondrial Calcium Overload and α-Synuclein Aggregation in Enteroendocrine Cells

Commensal Gut Bacterium Akkermansia Muciniphila Secretome Induces Mitochondrial Calcium Overload and α-Synuclein Aggregation in Enteroendocrine Cells

Calcium, Bioenergetics, and Parkinson’s Disease

Akkermansia muciniphilasecretome promotes α-synuclein aggregation in enteroendocrine cells

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