| 1. |
- Leal, NS, et al.
(author)
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Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models
- 2020
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In: Cells. - : MDPI AG. - 2073-4409. ; 9:12
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Journal article (peer-reviewed)abstract
- Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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| 2. |
- Dentoni, G, et al.
(author)
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Mitochondria-Endoplasmic Reticulum Interplay Regulates Exo-Cytosis in Human Neuroblastoma Cells
- 2022
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In: Cells. - : MDPI AG. - 2073-4409. ; 11:3
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Journal article (peer-reviewed)abstract
- Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the role of these contacts in exocytosis and find potential mechanisms linking these structures to vesicle release in human neuroblastoma SH-SY5Y cells. We show that increased mitochondria to ER juxtaposition through Mitofusin 2 (Mfn2) knock-down resulted in a substantial upregulation of the number of MERCS, confirming the role of Mfn2 as a negative regulator of these structures. Furthermore, we report that both vesicle numbers and vesicle protein levels were decreased, while a considerable upregulation in exocytotic events upon cellular depolarization was detected. Interestingly, in Mfn2 knock-down cells, the inhibition of the inositol 1,4,5-trisphosphate receptor (IP3R) and the mitochondrial calcium (Ca2+) uniporter (MCU) restored vesicle protein content and attenuated exocytosis. We thus suggest that MERCS could be targeted to prevent increased exocytosis in conditions in which ER to mitochondria proximity is upregulated.
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| 4. |
- Dentoni, G, et al.
(author)
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The Potential of Small Molecules to Modulate the Mitochondria-Endoplasmic Reticulum Interplay in Alzheimer's Disease
- 2022
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In: Frontiers in cell and developmental biology. - : Frontiers Media SA. - 2296-634X. ; 10, s. 920228-
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identified despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, inflammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria–endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology. Due to the variety of biological processes overseen at the MERCS, we believe that they constitute unique therapeutic targets to boost the neuronal function and recover neuronal homeostasis. Thus, developing molecules with the capacity to correct and/or modulate the MERCS interplay can unleash unique therapeutic opportunities for AD. The potential pharmacological intervention using MERCS modulators in different models of AD is currently under investigation. Here, we survey small molecules with the potential to modulate MERCS structures and functions and restore neuronal homeostasis in AD. We will focus on recently reported examples and provide an overview of the current challenges and future perspectives to develop MERCS modulators in the context of translational research.
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| 9. |
- Vaziri, Sam, et al.
(author)
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Bilayer insulator tunnel barriers for graphene-based vertical hot-electron transistors
- 2015
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In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3364 .- 2040-3372. ; 7:30, s. 13096-13104
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Journal article (peer-reviewed)abstract
- Vertical graphene-based device concepts that rely on quantum mechanical tunneling are intensely being discussed in the literature for applications in electronics and optoelectronics. In this work, the carrier transport mechanisms in semiconductor-insulator-graphene (SIG) capacitors are investigated with respect to their suitability as electron emitters in vertical graphene base transistors (GBTs). Several dielectric materials as tunnel barriers are compared, including dielectric double layers. Using bilayer dielectrics, we experimentally demonstrate significant improvements in the electron injection current by promoting Fowler-Nordheim tunneling (FNT) and step tunneling (ST) while suppressing defect mediated carrier transport. High injected tunneling current densities approaching 103 A cm(-2) (limited by series resistance), and excellent current-voltage nonlinearity and asymmetry are achieved using a 1 nm thick high quality dielectric, thulium silicate (TmSiO), as the first insulator layer, and titanium dioxide (TiO2) as a high electron affinity second layer insulator. We also confirm the feasibility and effectiveness of our approach in a full GBT structure which shows dramatic improvement in the collector on-state current density with respect to the previously reported GBTs. The device design and the fabrication scheme have been selected with future CMOS process compatibility in mind. This work proposes a bilayer tunnel barrier approach as a promising candidate to be used in high performance vertical graphene-based tunneling devices.
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| 10. |
- Vaziri, Sam, et al.
(author)
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Step tunneling-enhanced hot-electron injection in vertical graphene base transistors
- 2015
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In: European Solid-State Device Research Conference. - : Editions Frontieres. - 9781467371339 ; , s. 198-201
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Conference paper (peer-reviewed)abstract
- This paper presents promising current-voltage characteristics of semiconductor-insulator-graphene tunnel diodes as the hot-electron injection unit in graphene base transistors (GBTs). We propose that by using a bilayer tunnel barrier one can effectively suppress the defect mediated carrier transport while enhancing the hot-electron emission through Fowler-Nordheim tunneling (FNT) and step tunneling (ST). A stack of TmSiO/TiO2 (1 nm/ 5.5 nm) is sandwiched between a highly doped Si substrate and a single layer graphene (SLG) as the electrodes. This tunnel diode exhibits high current with large nonlinearity suitable for the application in GBTs.
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