115 research outputs found
Ruolo della proteasi mitocondriale Lonp1 nella regolazione della mitofagia
No full textLonp1 è una proteasi mitocondriale essenziale per l'omeostasi degli organelli e la risposta delle cellule allo stress. Lonp1 è indotta da diversi stimoli di stress, come l'ipossia, lo shock termico, lo stress ossidativo, il precondizionamento ischemico e la deplezione di nutrienti. Per questo motivo, Lonp1 potrebbe promuovere la sopravvivenza delle cellule tumorali favorendo la resistenza delle cellule allo stress. Il nostro gruppo ha in precedenza dimostrato che Lonp1 è upregolato nel cancro del colon-retto, rispetto alla mucosa normale, e che Lonp1 aumenta durante la progressione del cancro del colon.
Poiché abbiamo osservato che Lonp1 degrada selettivamente PINK1 e poiché è noto che HIF1- aumenta l'espressione di Lonp1, abbiamo studiato il possibile ruolo di Lonp1 nella regolazione della mitofagia, in condizioni di normossia e ipossia. Il silenziamento di Lonp1 aumenta i livelli di PINK1 e la sua localizzazione sulla membrana mitocondriale in presenza di CCCP, un noto induttore di mitofagia, mentre l’overespressione ha l'effetto opposto; non sono stati osservati cambiamenti in altre vie mitofagiche come ULK1 e FUNDC1. L'ipossia non altera questi effetti, ma abbiamo osservato che l’overespressione di Lonp1 modula i livelli di HIF-1 in condizioni di ipossia. L'assenza di Lonp1 e l'induzione della mitofagia da parte di CCCP causano una complessa alterazione delle proteine della dinamica mitocondriale, l'aumento dei livelli di specie reattive dell'ossigeno (ROS), la riduzione del potenziale di membrana mitocondriale e la compromissione della morfologia mitocondriale.
Studiando il ruolo di Lonp1 nella mitofagia, abbiamo osservato che Lonp1 è presente nel nucleo, e non solo nei mitocondri, e che i livelli nucleari aumentano in risposta allo shock termico. Quando nel nucleo, Lonp1 interagisce con il fattore di shock termico 1 (HSF1) e attenua la risposta HSF1-mediata.
Infine, abbiamo dimostrato la coesistenza di tre diverse isoforme di Lonp1, che abbiamo chiamato ISO1, l'isoforma completa e la più abbondante; ISO2, più corta nel dominio N-terminale e ISO3, la più corta, senza la sequenza di targeting mitocondriale (MTS). Esaminando TSVdb, un database di isoforme di splicing di geni umani abbiamo osservato che queste tre isoforme sono espresse in modo differente in diversi tessuti e che c’è un'upregolazione delle isoforme nei tumori. Queste isoforme hanno una diversa localizzazione subcellulare, ISO1 è quasi esclusivamente mitocondriale, ISO2 è presente sia nei mitocondri che nel citosol, mentre ISO3 non colocalizza con i mitocondri, in accordo con l'assenza di MTS. ISO1 e ISO2 sono modulati in modo diverso nel cancro, essendo ISO2 la forma che viene upregolata più frequentemente e a livelli più elevati. L’overespressione delle isoforme ha inoltre un impatto sulla respirazione mitocondriale, aumentandola rispetto al controllo, e modula l'aggressività del tumore.
In conclusione, il nostro studio ha evidenziato il coinvolgimento di Lonp1 nella regolazione della mitofagia, anche in ambiente ipossico. In particolare, abbiamo osservato modifiche nell'attivazione delle vie mitofagiche, nel turnover e nella morfologia mitocondriale e nella produzione di ROS quando Lonp1 è silenziato o upregolato. Inoltre, il nostro studio ha rivelato che Lonp1 può far parte di un meccanismo di regolazione con scambio nucleo-mitocondri in risposta allo shock e che Lonp1 esiste anche in forma extramitocondriale, principalmente a causa di diverse isoforme da splicing alternativo. L'espressione relativa delle isoforme influisce sulla respirazione e sul metabolismo mitocondriale. Queste osservazioni ampliano notevolmente l'elenco dei ruoli e delle funzioni di Lonp1, che vanno ben oltre quelli finora attribuiti a questa proteina.Lonp1 is a mitochondrial protease encoded by nuclear DNA essential for organelle homeostasis and cell response to stress. Lonp1 is induced by several stress stimuli, such as hypoxia, heat shock, ER and oxidative stress, ischemic preconditioning, nutrient depletion, and unfolded protein response. For this reason, Lonp1 could promote cancer cell survival favouring cell resistance to stress. Our group has previously shown that Lonp1 is upregulated in colorectal cancer, compared to the normal mucosal counterparts, and that Lonp1 increases during colon cancer progression.
As we observed that Lonp1 selectively degrades PINK1, and since it is known that HIF1-a enhances Lonp1 expression, we investigated the possible role of Lonp1 in regulating mitophagy, under normoxic and hypoxic conditions. Silencing of Lonp1 increases PINK1 levels and localization of PINK1 on mitochondrial membrane in the presence of CCCP, a well-known mitophagy inducer, while overexpression has the opposite effect; no changes were observed in other mitophagic pathways such as ULK1 and FUNDC1. Hypoxia does not alter these effects, but we observed that Lonp1 overexpression causes a reduction of HIF-1 levels under hypoxia. The absence of Lonp1 and the induction of mitophagy by CCCP causes a complex alteration of mitochondrial dynamics proteins, increase in reactive oxygen species (ROS) levels and mitochondrial membrane potential reduction, and mitochondrial morphology impairment.
While investigating Lonp1 modulation in mitophagy, we observed that Lonp1 is present in the nucleus, and not only in the mitochondria, and that nuclear levels increase in response to heat shock, but not to DNA damage or cell cycle arrest. When in the nucleus, Lonp1 interacts with Heat Shock Factor 1 (HSF1) and mitigates HSF1-mediated response. Thus, Lonp1 may be part of a regulatory mechanism with nucleus-mitochondria crosstalk in response to stress.
Finally, we showed three different isoforms of Lonp1 co-exist, that we named ISO1, the full-length isoform and the most abundant one; ISO2, slightly shorter at the N-domain and ISO3, the shortest one, without the mitochondrial targeting sequence (MTS). We inspected TSVdb, a database of splicing isoforms of human genes in normal and transformed cells and found that these three isoforms are differentially expressed in different tissues, and comparing normal and tumoral tissue, we can find an upregulation of the isoforms in tumor, except for ISO3. These three isoforms have different subcellular localization, as ISO1 is almost exclusively mitochondrial, ISO2 is present both in mitochondria and in the cytosol, while ISO3 does not colocalize with mitochondria, in agreement with the absence of MTS. Interestingly, ISO1 and ISO2 are differently modulated in cancer, being ISO2 the form that is upregulated more frequently and at higher levels.
The overexpression of the three isoforms impacts mitochondrial respiration by increasing it, comparing to control, and modulates tumour aggressiveness.
In conclusion, our study highlighted the involvement of Lonp1 in the regulation of mitophagy, also in a hypoxic environment. In particular, we showed modification in mitophagic pathways activation, mitochondrial turnover and morphology, and ROS production when Lonp1 is silenced or upregulated. Moreover, our study revealed that Lonp1 may be part of a regulatory mechanism with nucleus-mitochondria crosstalk in response to shock, and that Lonp1 also exists in extramitochondrial form, mainly due to different isoforms by alternative splicing. The relative expression of either form impacts mitochondrial respiration and metabolism. These observations greatly expand the list of roles and functions of Lonp1, which go far beyond those attributed to this protein so far
Indigenous peoples and climate justice. A critical analysis of international human rights law and governance
No full textThis book provides a new interpretation of international law specifically dedicated to Indigenous peoples in the context of a climate justice approach. The book presents a critical analysis of past and current developments at the intersection of human rights and international environmental law and governance. The book suggests new ways forward and demonstrates the need for a paradigmatic shift that would enhance the meaningful participation of Indigenous peoples as fundamental actors in the conservation of biodiversity and in the fight against climate change. The book offers guidance on a number of critical intersecting and interdependent issues at the forefront of climate change law and policy – inside and outside of the UN climate change regime. The author suggests that the adoption of a critical perspective on international law is needed in order to highlight inherent structural and systemic issues of the international law regime which are all issues that ultimately impede the pursue of climate justice for Indigenous peoples.
Giada Giacomini is an experienced researcher in international human rights law, international environmental law, climate change law and policy, and with an interest in climate vulnerable communities. She holds a PhD in Public, Comparative and International Law. She specializes in climate justice, critical legal studies and non-anthropocentric law. Upon completion of her PhD studies, she completed an Internship at the Independent Redress Mechanism of the Green Climate Fund. She is currently involved in several research projects dealing with ecosocial work, environmental conservation and Indigenous peoples, and climate litigation
Indigenous peoples and climate change. The Yanesha people’s case from a participatory justice perspective
No full textThis paper analyses the main results of the fieldwork conducted by the author for the purposes of determining the impacts of climate change in traditionally living Yanesha communities of the Palcazu, Peru. It gives an overview of the relationship between the Yanesha people and their sacred territory before delving into the data gathered during the fieldwork carried out in November 2018. It concludes by linking the Yanesha people’s case to the broader issue of climate justice, arguing that Indigenous peoples’ participatory rights should be at the centre of a fair and inclusive international and national climate governance regime that recognizes both their vulnerability and their role as agents of environmental conservation
Mitochondrial DNA as inflammatory DAMP: a warning of an aging immune system?
No full textSenescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed 'inflammaging', with increased levels of proinflammatory cytokines, both at the tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA - the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP-AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging
Orientarsi tra le nuvole: cartografie, atlanti e pratiche mappanti nel racconto a fumetti
No full textA partire dalla recente nascita della ‘comic book geography’ (Dittmer 2014), il contributo intende proporre la ‘comic book cartography’ come un’ulteriore linea di ricerca volta ad esplorare le contaminazioni tra fumetto e cartografia.
L’approccio transdisciplinare proposto si fonda sull’intersezione tra geografia e analisi geocritica, tra ‘comics studies’ e teoria cartografica post-rappresentazionale. Attraverso una lettura ‘carto-centrata’ di alcuni casi di studio italiani e internazionali, il fumetto viene inteso come una mappa che coinvolge autore e lettore in una vera e propria pratica di orientamento.
[Abstract eng] Orientating among the balloons: maps, atlases and mapping practices in comic books
Starting from the recently emerged field of ‘comic book geography’ (Dittmer 2014), the article proposes ‘comic book cartography’ as a further research line to explore the intersections bewteen comics and cartography.
The proposed transdisciplinary approach is based on the encounter between geography and geocriticism, comics studies and post-representational theories in cartography. Through a ‘carto-centred’ reading of both Italian and international case studies, the comic book is interpreted as a map inolving author and reader in an orientation practice
Playing it fashionably queer: Mae West's performing sexuality
No full text“Marriage is a fine institution, but I’m not ready for an institution”. With this challenging innuendo, the American actress and author Mae West offers an insight into gender performativity and heteronormativity through marriage in a period, the “Roaring Twenties”, in which sexual and gender politics could not be put into scrutiny. Her vamp persona and the elaborated iconography that she crafted on her character gave birth to a meticulous semiotics of the body that eventually undermined the American social context of the time fostering on the one hand, an image of heterosexual desire, and on the other hand an appealing icon to a gay market. This article ventures a queer-oriented perspective on West’s charismatic character and on the intertwined effects that tie semiotics to body language, especially focussing on the plays Sex (1926) and The Drag (1927)
Comic Book Cartographies: A Cartocentred Reading of 'City of Glass', the Graphic Novel
No full textThis paper responds to the call for a deeper theoretical and methodological
exchange between the disciplines involved in geohumanities research and
proposes comic books as an environment for interdisciplinary,
geo/cartographical and literary critical research practice. The analysis
considers the emerging field of ‘comic book geographies’ and suggests a
further opening to ‘comic book cartographies’. Hence, by referring to the
‘spatiocentred’ approaches emerging in literary theory and criticism, I
propose a ‘geocritical’ and ‘cartocentred’ reading of comics to explore the
‘cartographies of the comic book’. I individuate the peculiar map-like
features of comics’ spatial grammar to interpret the comic book as both a
cartographer and a map. Moreover, taking into account the recent shift in
cartographic theory towards an ‘emergent cartography’, I propose an
‘ontogenetic’ understanding of comics as maps. Through both their
representational and non-representational, map-like features, comics are
intended ‘as always mappings’, providing the author/reader with a truly
mapping experience. The analysis of the exemplary case study of City of
Glass, the graphic novel transposition of Auster’s novel by Paul Karasik and
David Mazzucchelli, counts as a first attempt to propose a ‘cartocentred’
reading of the cartographies inserted within and emerging from a comic
book. This article suggests that a ‘cartocritical’ reading of comics could
provide comic studies, cultural geography and literary theory with new
insights, as well as cartographic theory with an unexplored laboratory to
keep on ‘rethinking maps’ from an ‘emergent’ perspective
Physical Activity and Diet in Older Women: A Narrative Review
No full textPhysical activity and diet are essential for maintaining good health and preventing the development of non-communicable diseases, especially in the older adults. One aspect that is often over-looked is the different response between men and women to exercise and nutrients. The body’s response to exercise and to different nutrients as well as the choice of foods is different in the two sexes and is strongly influenced by the different hormonal ages in women. The present narrative review analyzes the effects of gender on nutrition and physical activity in older women. Understanding which components of diet and physical activity affect the health status of older women would help target non-pharmacological but lifestyle-related therapeutic interventions. It is interesting to note that this analysis shows a lack of studies dedicated to older women and a lack of studies dedicated to the interactions between diet and physical activity in women. Gender medicine is a current need that still finds little evidence
Modulation of Lonp1 Activity by Small Compounds
No full textThe Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance
Differential Expression of Lonp1 Isoforms in Cancer Cells
No full textLonp1 is a mitochondrial protease that degrades oxidized and damaged proteins, assists protein folding, and contributes to the maintenance of mitochondrial DNA. A higher expression of LonP1 has been associated with higher tumour aggressiveness. Besides the full-length isoform (ISO1), we identified two other isoforms of Lonp1 in humans, resulting from alternative splicing: Isoform-2 (ISO2) lacking aa 42-105 and isoform-3 (ISO3) lacking aa 1-196. An inspection of the public database TSVdb showed that ISO1 was upregulated in lung, bladder, prostate, and breast cancer, ISO2 in all the cancers analysed (including rectum, colon, cervical, bladder, prostate, breast, head, and neck), ISO3 did not show significant changes between cancer and normal tissue. We overexpressed ISO1, ISO2, and ISO3 in SW620 cells and found that the ISO1 isoform was exclusively mitochondrial, ISO2 was present in the organelle and in the cytoplasm, and ISO3 was exclusively cytoplasmatic. The overexpression of ISO1 and, at a letter extent, of ISO2 enhanced basal, ATP-linked, and maximal respiration without altering the mitochondria number or network, mtDNA amount. or mitochondrial dynamics. A higher extracellular acidification rate was observed in ISO1 and ISO2, overexpressing cells, suggesting an increase in glycolysis. Cells overexpressing the different isoforms did not show a difference in the proliferation rate but showed a great increase in anchorage-independent growth. ISO1 and ISO2, but not ISO3, determined an upregulation of EMT-related proteins, which appeared unrelated to higher mitochondrial ROS production, nor due to the activation of the MEK ERK pathway, but rather to global metabolic reprogramming of cells
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