α-Synuclein Controls Mitochondrial Calcium Homeostasis by Enhancing Endoplasmic Reticulum-Mitochondria Interactions

Calì, Tito; Ottolini, Denis; Negro, Alessandro; Brini, Marisa

doi:10.1074/jbc.m111.302794

Cited by 278 publications

(251 citation statements)

References 53 publications

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“…Later works by other authors reported similar values [4][5][6][7][8]. However, our data here indicate that [Ca 2+ ] ER is higher.…”

Section: Discussionsupporting

confidence: 71%

“…The first measurements of [Ca 2+ ] ER using mutated aequorin, reconstituted with a semi-synthetic coelenterazine with lower relative luminescence intensity (coelenterazine n), were made by us 15 years ago [1][2][3]. This combination of mutated aequorin and coelenterazine n (ER-mutAEQ-n) has been widely used to measure [Ca 2+ ] ER along these years [4][5][6][7][8]. However, it still has some problems that severely limit the results which can be obtained.…”

Section: Introductionmentioning

confidence: 99%

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Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

et al. 2013

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a b s t r a c tWe use here a new very low-Ca 2+ -affinity targeted aequorin to measure the [Ca 2+ ] between 0.1 and 3 mM, and was only partially affected by mitochondrial membrane depolarization. Instead, it was significantly reduced by loading cells with chelators, and the fast chelator BAPTA was much more effective than the slow chelator EGTA. This suggests that local [Ca 2+ ] microdomains connecting the store operated Ca 2+ channels with the ER Ca 2+ pumps may be important during refilling.

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“…Later works by other authors reported similar values [4][5][6][7][8]. However, our data here indicate that [Ca 2+ ] ER is higher.…”

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

et al. 2013

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“…Numerous recessively inherited forms of PD involve loss of function in proteins directly involved in mitochondrial maintenance, dynamics, or homeostasis, including Parkin, Pink1, and DJ-1 [312,313]. α-Synuclein may have a normal role in the mitochondria, such as maintenance of mitochondrial calcium homeostasis [314], whereas pathogenic α-synuclein may target mitochondria [121,[315][316][317][318] through direct interactions in a conformation or aggregation state-dependent fashion [319][320][321] or indirectly through activation of cell death pathways in which mitochondria play a critical role [120,228].…”

Section: Mitochondriamentioning

confidence: 99%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

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“…In normal conditions, α-syn is found in the cytosol where it regulates the dopamine synthesis pathway [ 116 ] and within mitochondria-associated ER membranes (MAMs) where it may participate in a number of key signaling pathways, including the regulation of mitochondrial Ca 2+ transients and mitochondrial dynamics [ 117 ]. PD-associated mitochondrial dysfunction induces α-syn [ 71 , 118 , 119 ], which may represent a retrograde signal designed to dampen the bioenergetic burden of synaptic transmission by blocking vesicle exocytosis and neurotransmitter release [ 120 ], to preserve neuronal Ca 2+ homeostasis at MAMs [ 117 ], or to decrease oxidative stress associated with dopamine autoxidation [ 116 ] within the PD brain [ 119 ].…”

Section: α-Synuclein To Lewy Bodiesmentioning

confidence: 99%

“…PD-associated mitochondrial dysfunction induces α-syn [ 71 , 118 , 119 ], which may represent a retrograde signal designed to dampen the bioenergetic burden of synaptic transmission by blocking vesicle exocytosis and neurotransmitter release [ 120 ], to preserve neuronal Ca 2+ homeostasis at MAMs [ 117 ], or to decrease oxidative stress associated with dopamine autoxidation [ 116 ] within the PD brain [ 119 ].…”

Section: α-Synuclein To Lewy Bodiesmentioning

confidence: 99%

Mitochondrial Signaling and Neurodegeneration

Picard

McManus

2016

Mitochondrial Dysfunction in Neurodegenerative Disorders

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The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic infl ammation, and protein aggregates, remain unclear.Emerging evidence demonstrates that mitochondria are not only power-generating organelles, but also engage in signaling at multiple levels. During the bioenergetic decline associated with aging, dysfunctional mitochondria generate signals of stress (SOS) that can trigger and/or amplify neurodegenerative processes. In this chapter, we describe emerging mechanisms for mitochondrial signaling at four different levels. Mitochondria communicate (1) with each other via fusion and specialized inter-mitochondrial junctions, (2) with cytoplasmic components via posttranslational modifi cations that shift signaling pathways and promote protein aggregation, (3) with the nucleus to regulate epigenetic modifi cations and gene expression, and (4) with the systemic environment where they alter neuroendocrine and infl ammatory processes that impact neuronal function. The relevance of mitochondrial signaling to neurodegeneration is discussed.

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α-Synuclein Controls Mitochondrial Calcium Homeostasis by Enhancing Endoplasmic Reticulum-Mitochondria Interactions

Cited by 278 publications

References 53 publications

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+-affinity targeted aequorin

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Mitochondrial Signaling and Neurodegeneration

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