Significance Accumulating evidence has underscored the role of cytosolic p53 in promoting cell death. Different reports have revealed that p53 participates in apoptosis induction by acting directly ...at mitochondria. However, because p53 can mediate apoptosis without its DNA-binding domain (the domain proposed to be fundamental for the targeting of p53 to mitochondria), the mitochondrial localization of p53 is likely not the only transcription-independent mechanism by which p53 promotes apoptosis. Here we demonstrate that p53 at the endoplasmic reticulum (ER) and at mitochondria-associated membranes, interacting with sarco/ER Ca ²⁺-ATPase pumps, modulates ER–mitochondria cross-talk and, in turn, Ca ²⁺-dependent apoptosis.
The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca ²⁺) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca ²⁺ homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca ²⁺-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca ²⁺ load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca ²⁺ overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca ²⁺ signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca ²⁺ signal-dependent apoptosis.
Calcium (Ca2+) homeostasis is fundamental for cell metabolism, proliferation, differentiation, and cell death. Elevation in intracellular Ca2+ concentration is dependent either on Ca2+ influx from ...the extracellular space through the plasma membrane, or on Ca2+ release from intracellular Ca2+ stores, such as the endoplasmic/sarcoplasmic reticulum (ER/SR). Mitochondria are also major components of calcium signalling, capable of modulating both the amplitude and the spatio-temporal patterns of Ca2+ signals. Recent studies revealed zones of close contact between the ER and mitochondria called MAMs (Mitochondria Associated Membranes) crucial for a correct communication between the two organelles, including the selective transmission of physiological and pathological Ca2+ signals from the ER to mitochondria. In this review, we summarize the most up-to-date findings on the modulation of intracellular Ca2+ release and Ca2+ uptake mechanisms. We also explore the tight interplay between ER- and mitochondria-mediated Ca2+ signalling, covering the structural and molecular properties of the zones of close contact between these two networks.
The recently discovered mitochondrial calcium uniporter (MCU) promotes Ca2+ accumulation into the mitochondrial matrix 1, 2. We identified in silico miR-25 as a cancer-related MCU-targeting microRNA ...family and demonstrate that its overexpression in HeLa cells drastically reduces MCU levels and mitochondrial Ca2+ uptake, while leaving other mitochondrial parameters and cytosolic Ca2+ signals unaffected. In human colon cancers and cancer-derived cells, miR-25 is overexpressed and MCU accordingly silenced. miR-25-dependent reduction of mitochondrial Ca2+ uptake correlates with resistance to apoptotic challenges and can be reversed by anti-miR-25 overexpression. Overall, the data demonstrate that microRNA targeting of mitochondrial Ca2+ signaling favors cancer cell survival, thus providing mechanistic insight into the role of mitochondria in tumorigenesis and identifying a novel therapeutic target in neoplasia.
► miR-25 regulates intracellular calcium homeostasis ► Mitochondrial calcium uniporter (MCU) is a target of miR-25 ► MCU plays a critical role in apoptosis and tumorigenesis ► MCU is downregulated in different cancer cell lines and in human colonic adenocarcinoma
The precise molecular mechanisms that coordinate apoptosis and autophagy in cancer remain to be determined. Here, we provide evidence that the tumor suppressor promyelocytic leukemia protein (PML) ...controls autophagosome formation at mitochondria-associated membranes (MAMs) and, thus, autophagy induction. Our in vitro and in vivo results demonstrate how PML functions as a repressor of autophagy. PML loss promotes tumor development, providing a growth advantage to tumor cells that use autophagy as a cell survival strategy during stress conditions. These findings demonstrate that autophagy inhibition could be paired with a chemotherapeutic agent to develop anticancer strategies for tumors that present PML downregulation.
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•PML regulates autophagic processes from ER/MAM domains in a Ca2+-dependent manner•Localization of PML away from the MAMs is dependent on p53•Activation of autophagy by PML depletion promotes survival under stress conditions•Block of autophagy restores the activity of chemotherapy in PML-downregulated tumors
Missiroli et al. demonstrate that the tumor suppressor promyelocytic leukemia protein (PML) works as a repressor of autophagy by controlling autophagosome formation at mitochondria-associated membranes (MAMs) in a p53-dependent manner. Together, their studies generate alternative anticancer strategies for tumors that present PML downregulation.
Hormones, growth factors, electrical stimulation, and cell-cell interactions regulate numerous cellular processes by altering the levels of second messengers, thus influencing biochemical reactions ...inside the cells. The Protein Kinase C family (PKCs) is a group of serine/threonine kinases that are dependent on calcium (Ca(2+)), diacylglycerol, and phospholipids. Signaling pathways that induce variations on the levels of PKC activators have been implicated in the regulation of diverse cellular functions and, in turn, PKCs are key regulators of a plethora of cellular processes, including proliferation, differentiation, and tumorigenesis. Importantly, PKCs contain regions, both in the N-terminal regulatory domain and in the C-terminal catalytic domain, that are susceptible to redox modifications. In several pathophysiological conditions when the balance between oxidants, antioxidants, and alkylants is compromised, cells undergo redox stress. PKCs are cell-signaling proteins that are particularly sensitive to redox stress because modification of their redox-sensitive regions interferes with their activity and, thus, with their biological effects. In this review, we summarize the involvement of PKCs in health and disease and the importance of redox signaling in the regulation of this family of kinases.
•West Nile virus recently caused outbreaks in Europe and Italy.•Neuroinvasive disease can lead to high mortality and morbidity in vulnerable population.•Early diagnosis and management can limit the ...negative effect of infection and unfavorable outcomes.
West Nile virus (WNV) recently caused recurrent outbreaks in Europe and Italy, and the occurrence of neuroinvasive disease (WNND) was observed in less than 1% of cases, mainly older patients with several comorbidities. Due to the high mortality and post-infectious sequelae, the prognosis of this illness was frequently poor.
In this case-series we reported the clinical outcomes of 7 patients hospitalized for WNND in the summer 2023 in our center of Infectious Disease in Vercelli, Italy.
Patients were generally older and affected by several comorbidities; at hospital admission fever and postural instability were most common symptoms; mortality rate observed was 42.8%; presence of neurological sequelae was detected in 28.6%. Diagnostic PCR for WNV was performed on cerebrospinal fluid (CSF) in 42.8% and urine sample in 57.1%. Treatment is supportive or with corticosteroids.
WNND is a severe illness that may affect a vulnerable population especially in the summer period and requires a prompt diagnosis and knowledge of clinical characteristics and risk factors. Environmental intervention are required in the control of spread of mosquito vectors.
Protein phosphorylation controls many aspects of cell fate and is often deregulated in pathological conditions. Several recent findings have provided an intriguing insight into the spatial regulation ...of protein phosphorylation across different subcellular compartments and how this can be finely orchestrated by specific kinases and phosphatases. In this review, the focus will be placed on (i) the phosphoinositide 3-kinase (PI3K) pathway, specifically on the kinases Akt and mTOR and on the phosphatases PP2a and PTEN, and on (ii) the PKC family of serine/threonine kinases. We will look at general aspects of cell physiology controlled by these kinases and phosphatases, highlighting the signalling pathways that drive cell division, proliferation, and apoptosis.
To date the optimal antiviral treatment against severe coronavirus disease 2019 (COVID‐19) has not been proven; remdesivir is a promising drug with in vitro activity against several viruses, but in ...COVID‐19 the clinical results are currently not definitive. In this retrospective observational study, we analyzed the clinical outcomes (survival analysis, efficacy, and safety) in a group of hospitalized patients with COVID‐19 treated with remdesivir in comparison with a control group of patients treated with other antiviral or supportive therapies. We included 163 patients treated with remdesivir and 403 subjects in the control group; the baseline characteristics were similar in the two groups; the mortality rate was higher in the control group (24.8% vs. 2.4%, p < 0.001), the risk of intensive care unit (ICU) admission was higher in the control group (17.8% vs. 9.8%, p = 0.008); hospitalization time was significantly lower in patients treated with remdesivir (9.5 vs. 12.5 days, p < 0.001). The safety of remdesivir was good and no significant adverse events were reported. In multivariate analysis, the remdesivir treatment was independently associated with a 34% lower mortality rate (odds ratio = 0.669; p = 0.014). In this analysis, the treatment with remdesivir was associated with lower mortality, lower rate of ICU admission, and shorter time of hospitalization. No adverse events were observed. This promising antiviral treatment should also be confirmed by other studies.
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