Publications by authors named "Alberto Danese"

15 Publications

  • Page 1 of 1

Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases.

Biomedicines 2021 Feb 4;9(2). Epub 2021 Feb 4.

Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.

During the past few decades, considerable efforts have been made to discover and validate new molecular mechanisms and biomarkers of neurodegenerative diseases. Recent discoveries have demonstrated how autophagy and its specialized form mitophagy are extensively associated with the development, maintenance, and progression of several neurodegenerative diseases. These mechanisms play a pivotal role in the homeostasis of neural cells and are responsible for the clearance of intracellular aggregates and misfolded proteins and the turnover of organelles, in particular, mitochondria. In this review, we summarize recent advances describing the importance of autophagy and mitophagy in neurodegenerative diseases, with particular attention given to multiple sclerosis, Parkinson's disease, and Alzheimer's disease. We also review how elements involved in autophagy and mitophagy may represent potential biomarkers for these common neurodegenerative diseases. Finally, we examine the possibility that the modulation of autophagic and mitophagic mechanisms may be an innovative strategy for overcoming neurodegenerative conditions. A deeper knowledge of autophagic and mitophagic mechanisms could facilitate diagnosis and prognostication as well as accelerate the development of therapeutic strategies for neurodegenerative diseases.
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http://dx.doi.org/10.3390/biomedicines9020149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913851PMC
February 2021

Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer.

Int J Mol Sci 2020 Nov 6;21(21). Epub 2020 Nov 6.

Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.

Calcium (Ca) is a major second messenger in cells and is essential for the fate and survival of all higher organisms. Different Ca channels, pumps, or exchangers regulate variations in the duration and levels of intracellular Ca, which may be transient or sustained. These changes are then decoded by an elaborate toolkit of Ca-sensors, which translate Ca signal to intracellular operational cell machinery, thereby regulating numerous Ca-dependent physiological processes. Alterations to Ca homoeostasis and signaling are often deleterious and are associated with certain pathological states, including cancer. Altered Ca transmission has been implicated in a variety of processes fundamental for the uncontrolled proliferation and invasiveness of tumor cells and other processes important for cancer progression, such as the development of resistance to cancer therapies. Here, we review what is known about Ca signaling and how this fundamental second messenger regulates life and death decisions in the context of cancer, with particular attention directed to cell proliferation, apoptosis, and autophagy. We also explore the intersections of Ca and the therapeutic targeting of cancer cells, summarizing the therapeutic opportunities for Ca signal modulators to improve the effectiveness of current anticancer therapies.
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http://dx.doi.org/10.3390/ijms21218323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664196PMC
November 2020

Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies.

Cell Calcium 2020 12 16;92:102308. Epub 2020 Oct 16.

Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy. Electronic address:

As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.
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http://dx.doi.org/10.1016/j.ceca.2020.102308DOI Listing
December 2020

Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs).

Rev Physiol Biochem Pharmacol 2020 Aug 14. Epub 2020 Aug 14.

Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca) signals, this particular interaction controls several Ca-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca signaling.
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http://dx.doi.org/10.1007/112_2020_43DOI Listing
August 2020

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.

Sci Rep 2020 03 16;10(1):4785. Epub 2020 Mar 16.

IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria.
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http://dx.doi.org/10.1038/s41598-020-61735-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075867PMC
March 2020

Deficiency of Mitochondrial Aspartate-Glutamate Carrier 1 Leads to Oligodendrocyte Precursor Cell Proliferation Defects Both In Vitro and In Vivo.

Int J Mol Sci 2019 Sep 11;20(18). Epub 2019 Sep 11.

Department of Pharmacy and BioTechnology, University of Bologna, 40126 Bologna, Italy.

Aspartate-Glutamate Carrier 1 (AGC1) deficiency is a rare neurological disease caused by mutations in the solute carrier family 25, member 12 () gene, encoding for the mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), a component of the malate-aspartate NADH shuttle (MAS), expressed in excitable tissues only. AGC1 deficiency patients are children showing severe hypotonia, arrested psychomotor development, seizures and global hypomyelination. While the effect of AGC1 deficiency in neurons and neuronal function has been deeply studied, little is known about oligodendrocytes and their precursors, the brain cells involved in myelination. Here we studied the effect of AGC1 down-regulation on oligodendrocyte precursor cells (OPCs), using both in vitro and in vivo mouse disease models. In the cell model, we showed that a reduced expression of AGC1 induces a deficit of OPC proliferation leading to their spontaneous and precocious differentiation into oligodendrocytes. Interestingly, this effect seems to be related to a dysregulation in the expression of trophic factors and receptors involved in OPC proliferation/differentiation, such as Platelet-Derived Growth Factor α (PDGFα) and Transforming Growth Factor βs (TGFβs). We also confirmed the OPC reduction in vivo in AGC1-deficent mice, as well as a proliferation deficit in neurospheres from the Subventricular Zone (SVZ) of these animals, thus indicating that AGC1 reduction could affect the proliferation of different brain precursor cells. These data clearly show that AGC1 impairment alters myelination not only by acting on N-acetyl-aspartate production in neurons but also on OPC proliferation and suggest new potential therapeutic targets for the treatment of AGC1 deficiency.
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http://dx.doi.org/10.3390/ijms20184486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769484PMC
September 2019

Mitochondrial calcium uniporter complex modulation in cancerogenesis.

Cell Cycle 2019 05 10;18(10):1068-1083. Epub 2019 May 10.

a Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology , Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara , Ferrara , Italy.

Aberrations in mitochondrial Ca homeostasis have been associated with different pathological conditions, including neurological defects, cardiovascular diseases, and, in the last years, cancer. With the recent molecular identification of the mitochondrial calcium uniporter (MCU) complex, the channel that allows Ca accumulation into the mitochondrial matrix, alterations in the expression levels or functioning in one or more MCU complex members have been linked to different cancers and cancer-related phenotypes. In this review, we will analyze the role of the uniporter and mitochondrial Ca derangements in modulating cancer cell sensitivity to death, invasiveness, and migratory capacity, as well as cancer progression in vivo. We will also discuss some critical points and contradictory results to highlight the consequence of MCU complex modulation in tumor development.
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http://dx.doi.org/10.1080/15384101.2019.1612698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592253PMC
May 2019

ER-mitochondria cross-talk is regulated by the Ca sensor NCS1 and is impaired in Wolfram syndrome.

Sci Signal 2018 10 23;11(553). Epub 2018 Oct 23.

Institute of Neurosciences of Montpellier, INSERM, University of Montpellier, 34090 Montpellier, France.

Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IPR) to promote Ca transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.
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http://dx.doi.org/10.1126/scisignal.aaq1380DOI Listing
October 2018

Role of Mitochondria-Associated ER Membranes in Calcium Regulation in Cancer-Specific Settings.

Neoplasia 2018 05 5;20(5):510-523. Epub 2018 Apr 5.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA center, University of Ferrara, Ferrara, Italy; Cecilia Hospital, GVM Care & Research, E.S.: Health Science Foundation, Cotignola, Italy; CNR Institute of Cell Biology and Neurobiology, Monterotondo, Italy. Electronic address:

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term "cancer" denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective.
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http://dx.doi.org/10.1016/j.neo.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916088PMC
May 2018

Calcium Dynamics as a Machine for Decoding Signals.

Trends Cell Biol 2018 04 3;28(4):258-273. Epub 2018 Feb 3.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy; Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation, Cotignola, Italy; CNR Institute of Cell Biology and Neurobiology, Monterotondo, Italy. Electronic address:

Calcium (Ca) is considered one of the most-important biological cations, because it is implicated in cell physiopathology and cell fate through a finely tuned signaling system. In support of this notion, Ca is the primary driver of cell proliferation and cell growth; however, it is also intimately linked to cell death. Functional abnormalities or mutations in proteins that mediate Ca homeostasis usually lead to a plethora of diseases and pathogenic states, including cancer, heart failure, diabetes, and neurodegenerative disease. In this review, we examine recent discoveries in the highly localized nature of Ca-dependent signal transduction and its roles in cell fate, inflammasome activation, and synaptic transmission.
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http://dx.doi.org/10.1016/j.tcb.2018.01.002DOI Listing
April 2018

BAP1 regulates IP3R3-mediated Ca flux to mitochondria suppressing cell transformation.

Nature 2017 06 14;546(7659):549-553. Epub 2017 Jun 14.

University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813 USA.

BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1) developed one and often several BAP1 malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 carriers cause reduction both of IP3R3 levels and of Ca flux, preventing BAP1 cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1 carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
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http://dx.doi.org/10.1038/nature22798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581194PMC
June 2017

Down-regulation of the mitochondrial aspartate-glutamate carrier isoform 1 AGC1 inhibits proliferation and N-acetylaspartate synthesis in Neuro2A cells.

Biochim Biophys Acta Mol Basis Dis 2017 06 21;1863(6):1422-1435. Epub 2017 Feb 21.

Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, Bari 70126, Italy. Electronic address:

The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS. Here, we show that undifferentiated Neuro2A cells with down-regulated AGC1 display a significant proliferation deficit associated with reduced mitochondrial respiration, and are unable to synthesize NAA properly. In the presence of high glutamine oxidation, cells with reduced AGC1 restore cell proliferation, although oxidative stress increases and NAA synthesis deficit persists. Our data suggest that the cellular energetic deficit due to AGC1 impairment is associated with inappropriate aspartate levels to support neuronal proliferation when glutamine is not used as metabolic substrate, and we propose that delayed myelination in AGC1 deficiency patients could be attributable, at least in part, to neuronal loss combined with lack of NAA synthesis occurring during the nervous system development.
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http://dx.doi.org/10.1016/j.bbadis.2017.02.022DOI Listing
June 2017

Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs).

Biochim Biophys Acta Bioenerg 2017 Aug 10;1858(8):615-627. Epub 2017 Jan 10.

Dept. of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy. Electronic address:

Until 1972, the term 'apoptosis' was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis. Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca) release from the ER allows selective Ca uptake by the mitochondria. The perturbation of Ca homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
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http://dx.doi.org/10.1016/j.bbabio.2017.01.003DOI Listing
August 2017

Endoplasmic reticulum-mitochondria Ca crosstalk in the control of the tumor cell fate.

Biochim Biophys Acta Mol Cell Res 2017 Jun 4;1864(6):858-864. Epub 2017 Jan 4.

Dept. of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy. Electronic address:

Mitochondria-associated membranes are juxtaposed between the endoplasmic reticulum and mitochondria and have been identified as a critical hub in the regulation of apoptosis and tumor growth. One key function of mitochondria-associated membranes is to provide asylum to a number of proteins with tumor suppressor and oncogenic properties. In this review, we discuss how Ca flux manipulation represents the primary mechanism underlying the action of several oncogenes and tumor-suppressor genes and how these networks might be manipulated to provide novel therapies for cancer. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
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http://dx.doi.org/10.1016/j.bbamcr.2016.12.024DOI Listing
June 2017