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Marinella Pirozzi

Institute for Experimental Endocrinology and Oncology

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Seetharaman Parashuraman

National Research Council

Alberto Luini

National Research Council

Gabriele Turacchio

Institute for Experimental Endocrinology and Oncology

Raviranjan Pandey

Indian Institute of Science Education and Research Kolkata

Saptarshi Maji

Indian Institute of Science Education and Research Kolkata

Ruturaj

Indian Institute of Science Education and Research Kolkata

Riccardo Rizzo

Istituto di Nanotecnologia

Santanu Das

Indian Institute of Science Education and Research Kolkata

Arnab Gupta

Indian Institute of Science Education and Research Kolkata

Vivek Malhotra

Centre for Genomic Regulation

Cooperative Institutions

John Wiley & Sons (United States)

Bioengineering Center

National Center for Genetic Engineering and Biotechnology

University of Naples Federico II

Hudson Institute

Federico II University Hospital

National Research Council

Institute of Protein Biochemistry

National Academies of Sciences, Engineering, and Medicine

Institute for Experimental Endocrinology and Oncology

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Author response for "Copper‐independent lysosomal localisation of the Wilson disease protein ATP7B"

Saptarshi Maji Marinella Pirozzi Ruturaj Raviranjan Pandey Tamal Kanti Ghosh

Wilson's disease

10.1111/tra.12919/v2/response1

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Abnormal autophagy, ubiquitination, inflammation and apoptosis are dependent upon lysosomal storage and are useful biomarkers of mucopolysaccharidosis VI

PathoGenetics (2009)

Alessandra Tessitore Marinella Pirozzi Alberto Auricchio

Lysosomal storage diseases are characterized by intracellular accumulation of metabolites within lysosomes. Recent evidence suggests that lysosomal storage impairs autophagy resulting in accumulation of polyubiquitinated proteins and dysfunctional mitochondria, ultimately leading to apoptosis. We studied the relationship between lysosome storage and impairment of different intracellular pathways and organelle function in mucopolysaccharidosis VI, which is characterized by accumulation of dermatan sulfate and signs of visceral and skeletal but not cerebral involvement.We show lysosomal storage, impaired autophagy, accumulation of polyubiquitinated proteins, and mitochondrial dysfunction in fibroblasts from mucopolysaccharidosis VI patients. We observe similar anomalies, along with inflammation and cell death, in association with dermatan sulfate storage in the visceral organs of mucopolysaccharidosis VI rats, but not in their central nervous system where dermatan sulfate storage is absent. Importantly, we show that prevention of dermatan sulfate storage in the mucopolysaccharidosis VI rat visceral organs by gene transfer results in correction of abnormal autophagy, inflammation, and apoptosis, suggesting that dermatan sulfate accumulation impairs lysosomal ability to receive and degrade molecules and organelles from the autophagic pathway, thus leading to cell toxicity.These results indicate that the non-lysosomal degradation pathways we found activated in mucopolysaccharidosis VI can be both targets of new experimental therapies and biomarkers for follow-up of existing treatments.

Dermatan sulfate

Mucopolysaccharidosis

Lysosomal storage disease

10.1186/1755-8417-2-4

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Citations (94)

Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells

Scientific Reports (2024)

Maria Rosaria Ambrosio Michiel Adriaens Kasper Derks Teresa Migliaccio Valerio Costa

An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. To explore BC-adipocytes interaction and define the impact of glucose in such dialogue, Mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER+ BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). The transcriptome of both cell types in co-culture as in mono-culture was profiled by RNA-Seq to define the impact of adipocytes on BC cells and viceversa (i), the action of glucose on BC cells, adipocytes (ii) and their crosstalk (iii). Noteworthy, we provided evidence that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, our data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients.

Reprogramming

Reciprocal

10.1038/s41598-024-76522-7

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Akap1 Regulates Vascular Function and Endothelial Cells Behavior

Hypertension (2018)

Gabriele G. Schiattarella Fabio Cattaneo Albino Carrizzo Roberta Paolillo Nicola Boccella

MitoAKAPs (mitochondrial A kinase anchoring proteins), encoded by the Akap1 gene, regulate multiple cellular processes governing mitochondrial homeostasis and cell viability. Although mitochondrial alterations have been associated to endothelial dysfunction, the role of mitoAKAPs in the vasculature is currently unknown. To test this, postischemic neovascularization, vascular function, and arterial blood pressure were analyzed in Akap1 knockout mice (Akap1-/- ) and their wild-type (wt) littermates. Primary cultures of aortic endothelial cells (ECs) were also obtained from Akap1-/- and wt mice, and ECs migration, proliferation, survival, and capillary-like network formation were analyzed under different experimental conditions. After femoral artery ligation, Akap1-/- mice displayed impaired blood flow and functional recovery, reduced skeletal muscle capillary density, and Akt phosphorylation compared with wt mice. In Akap1-/- ECs, a significant enhancement of hypoxia-induced mitophagy, mitochondrial dysfunction, reactive oxygen species production, and apoptosis were observed. Consistently, capillary-like network formation, migration, proliferation, and AKT phosphorylation were reduced in Akap1-/- ECs. Alterations in Akap1-/- ECs behavior were also confirmed in Akap1-/- mice, which exhibited a selective reduction in acetylcholine-induced vasorelaxation in mesenteric arteries and a mild but significant increase in arterial blood pressure levels compared with wt. Finally, overexpression of a constitutively active Akt mutant restored vascular reactivity and ECs function in Akap1-/- conditions. These results demonstrate the important role of mitoAKAPs in the modulation of multiple ECs functions in vivo and in vitro, suggesting that mitochondria-dependent regulation of ECs might represent a novel therapeutic approach in cardiovascular diseases characterized by endothelial dysfunction.

Arteriogenesis

Endothelial Dysfunction

Mesenteric arteries

10.1161/hypertensionaha.117.10185

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Citations (39)

TSLP is localized in and released from human lung macrophages activated by T2-high and T2-low stimuli: relevance in asthma and COPD

European Journal of Internal Medicine (2024)

Luisa Canè Remo Poto Francesco Palestra Marinella Pirozzi Seetharaman Parashuraman

Relevance

Human lung

10.1016/j.ejim.2024.02.020

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Citations (10)

TANGO1 assembles into rings around COPII coats at ER exit sites

The Journal of Cell Biology (2017)

Ishier Raote M. Bellido Marinella Pirozzi Chong Zhang D. Melville

TANGO1 (transport and Golgi organization 1) interacts with CTAGE5 and COPII components Sec23/Sec24 and recruits ERGIC-53 (endoplasmic reticulum [ER]–Golgi intermediate compartment 53)–containing membranes to generate a mega-transport carrier for export of collagens and apolipoproteins from the ER. We now show that TANGO1, at the ER, assembles in a ring that encircles COPII components. The C-terminal, proline-rich domains of TANGO1 molecules in the ring are initially tilted onto COPII coats but appear to be pushed apart as the carrier grows. These findings lend support to our suggestion that growth of transport carriers for exporting bulky cargoes requires addition of membranes and not simply COPII-mediated accretion of a larger surface of ER. TANGO1 remains at the neck of the newly forming transport carrier, which grows in size by addition of ERGIC-53–containing membranes to generate a transport intermediate for the export of bulky collagens.

COPII

Vesicular Transport Proteins

COPI

10.1083/jcb.201608080

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Citations (81)

Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice

Autophagy (2015)

Martina Chrisam Marinella Pirozzi Silvia Castagnaro Bert Blaauw Roman Polishchuck

Autophagy is a self-degradative process responsible for the clearance of damaged or unnecessary cellular components. We have previously found that persistence of dysfunctional organelles due to autophagy failure is a key event in the pathogenesis of COL6/collagen VI-related myopathies, and have demonstrated that reactivation of a proper autophagic flux rescues the muscle defects of Col6a1-null (col6a1(-/-)) mice. Here we show that treatment with spermidine, a naturally occurring nontoxic autophagy inducer, is beneficial for col6a1(-/-) mice. Systemic administration of spermidine in col6a1(-/-) mice reactivated autophagy in a dose-dependent manner, leading to a concurrent amelioration of the histological and ultrastructural muscle defects. The beneficial effects of spermidine, together with its being easy to administer and the lack of overt side effects, open the field for the design of novel nutraceutical strategies for the treatment of muscle diseases characterized by autophagy impairment.

Collagen VI

Muscle disorder

10.1080/15548627.2015.1108508

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Citations (76)

Copper‐independent lysosomal localisation of the Wilson disease protein ATP7B

Saptarshi Maji Marinella Pirozzi Ruturaj Raviranjan Pandey Tamal Kanti Ghosh

Abstract In hepatocytes, the Wilson disease protein ATP7B resides on the trans ‐Golgi network (TGN) and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in the endolysosomal compartment of hepatocytes but not in non‐hepatic cells. These ATP7B‐harbouring lysosomes lie in close proximity of ~10 nm to the TGN. ATP7B constitutively distributes itself between the sub‐domain of the TGN with a lower pH and the TGN‐proximal lysosomal compartments. The presence of ATP7B on TGN‐lysosome colocalising sites upon Golgi disruption suggested a possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localisation of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper‐replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN‐proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper‐independent lysosomal localisation of ATP7B and the importance of TGN‐proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway.

Organelle

Rab

Transport protein

ATP7A

10.1111/tra.12919

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Citations (2)

Copper-independent lysosomal localization of the Wilson disease protein ATP7B

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Saptarshi Maji Marinella Pirozzi Ruturaj Raviranjan Pandey Tamal Ghosh

Abstract In hepatocytes, the Wilson disease protein ATP7B resides on trans-Golgi network and traffics to peripheral lysosomes to export excess intracellular copper through lysosomal exocytosis. We found that in basal copper or even upon copper chelation, a significant amount of ATP7B persists in endolysosomal compartment of hepatocytes but not in non-hepatic cells. These ATP7B-harboring lysosomes lie in close proximity of ∼10nm to the TGN. ATP7B constitutively distributes itself between the sub-domain of the TGN with a lower pH and the TGN-proximal lysosomal compartments. Presence of ATP7B on TGN-Lysosome colocalizing sites upon Golgi disruption suggested possible exchange of ATP7B directly between the TGN and its proximal lysosomes. Manipulating lysosomal positioning significantly alters the localization of ATP7B in the cell. Contrary to previous understanding, we found that upon copper chelation in a copper-replete hepatocyte, ATP7B is not retrieved back to TGN from peripheral lysosomes; rather, ATP7B recycles to these TGN-proximal lysosomes to initiate the next cycle of copper transport. We report a hitherto unknown copper-independent lysosomal localization of ATP7B and the importance of TGN-proximal lysosomes but not TGN as the terminal acceptor organelle of ATP7B in its retrograde pathway. Synopsis Excess copper is toxic to the cell. In hepatocytes, the Wilson disease protein ATP7B has been reported to recycle between the trans-Golgi network and lysosomes to export copper in elevated copper conditions. We, for the first time, show that a large fraction of ATP7B constitutively resides on the lysosome and rather, the position of the lysosome shifts from TGN-proximal to the peripheral region of the cell in high copper to facilitate ATP7B-mediated lysosomal exocytosis of copper.

Organelle

Rab

Transport protein

Wilson's disease

10.1101/2022.10.30.514457

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Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Journal of Clinical Investigation (2004)

Fátima Ferreirinha Angelo Quattrini Marinella Pirozzi Valentina Valsecchi Giorgia Dina

In several neurodegenerative diseases, axonal degeneration occurs before neuronal death and contributes significantly to patients’ disability. Hereditary spastic paraplegia (HSP) is a genetically heterogeneous condition characterized by selective degeneration of axons of the corticospinal tracts and fasciculus gracilis. HSP may therefore be considered an exemplary disease to study the local programs mediating axonal degeneration. We have developed a mouse model for autosomal recessive HSP due to mutations in the SPG7 gene encoding the mitochondrial ATPase paraplegin. Paraplegin-deficient mice are affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. We found that mitochondrial morphological abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment during a rotarod test. Axonal swellings occur through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport is delayed in symptomatic mice. We speculate that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. Our data suggest that a timely therapeutic intervention may prevent the loss of axons.

Axoplasmic transport

Axonal Degeneration

Degeneration (medical)

Hereditary Spastic Paraplegia

Neurofilament

10.1172/jci20138

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Citations (263)