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Abstract Background Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model. Methods In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves. Results After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076). Conclusions Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

Abstract Intercellular adhesion is a key function for epithelial cells. The fundamental mechanisms relying on epithelial cell adhesion have been partially uncovered. Hsa-microRNA-1249-3p (hsa-miR-1249-3p) plays a role in the epithelial mesenchymal transition in carcinoma cells, but its physiological function in epithelial cells is unknown. We aimed to investigate the role and molecular mechanisms of hsa-miR-1249-3p on epithelial cell functions. Hsa-miR-1249-3p was overexpressed in human epithelial cells and uterine cervical tissues, compared to cervical carcinoma cells and precancerous tissues, respectively. Hsa-miR-1249-3p was analyzed to verify its regulatory function on Homeobox A13 (HOXA13) target gene and its downstream cell adhesion gene β-catenin. Functional experiments indicated that hsa-miR-1249-3p inhibition prompted the mRNA and protein overexpression of HOXA13 which, in turn, led to the β-catenin protein expression. Moreover, hsa-miR-1249-3p inhibition induced a strong colony forming ability in epithelial cells, suggesting the miR involvement in cell adhesion machinery. These data indicate that hsa-miR-1249-3p regulates the expression of HOXA13 and its downstream cell adhesion gene β-catenin, possible resulting in cell adhesion modification in epithelial cells. This study will allow the set-up of further investigations aimed at exploring the relationship between the hsa-miR-1249-3p/HOXA13 axis and downstream cell adhesion genes.

Neuronal disorders are associated with a profound loss of mitochondrial functions caused by various stress conditions, such as oxidative and metabolic stress, protein folding or import defects, and mitochondrial DNA alteration. Cells engage in different coordinated responses to safeguard mitochondrial homeostasis. In this review, we will explore the contribution of mitochondrial stress responses that are activated by the organelle to perceive these dangerous conditions, keep them under control and rescue the physiological condition of nervous cells. In the sections to come, particular attention will be dedicated to analyzing how compensatory mitochondrial hyperfusion, mitophagy, mitochondrial unfolding protein response, and apoptosis impact human neuronal diseases. Finally, we will discuss the relevance of the new concept: the “mito-inflammation”, a mitochondria-mediated inflammatory response that is recently found to cover a relevant role in the pathogenesis of diverse inflammatory-related diseases, including neuronal disorders.

Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

Mitochondria are organelles present in almost all eukaryotic cells, where they represent the main site of energy production. Mitochondria are involved in several important cell processes, such as calcium homeostasis, OXPHOS, autophagy, and apoptosis. Moreover, they play a pivotal role also in inflammation through the inter-organelle and inter-cellular communications, mediated by the release of mitochondrial damage-associated molecular patterns (mtDAMPs). It is currently well-documented that in addition to traditional endocrine and paracrine communication, the cells converse via extracellular vesicles (EVs). These small membrane-bound particles are released from cells in the extracellular milieu under physio-pathological conditions. Importantly, EVs have gained much attention for their crucial role in inter-cellular communication, translating inflammatory signals into recipient cells. EVs cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Studies have shown that EVs may transport mitochondrial portions, proteins, and/or mtDAMPs to modulate the metabolic and inflammatory responses of recipient cells. Overall, the relationship between EVs and mitochondria in inflammation is an active area of research, although further studies are needed to fully understand the mechanisms involved and how they may be targeted for therapeutic purposes. Here, we have reported and discussed the latest studies focused on this fascinating and recent area of research, discussing of tricky connection between mitochondria and EVs in inflammatory-related diseases.

The aims of this systematic literature review (SLR) were to identify the effects of approved biological and targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs) on synovial membrane of psoriatic arthritis (PsA) patients, and to determine the existence of histological/molecular biomarkers of response to therapy. A search was conducted on MEDLINE, Embase, Scopus, and Cochrane Library (PROSPERO:CRD42022304986) to retrieve data on longitudinal change of biomarkers in paired synovial biopsies and in vitro studies. A meta-analysis was conducted by adopting the standardized mean difference (SMD) as a measure of the effect. Twenty-two studies were included (19 longitudinal, 3 in vitro). In longitudinal studies, TNF inhibitors were the most used drugs, while, for in vitro studies, JAK inhibitors or adalimumab/secukinumab were assessed. The main technique used was immunohistochemistry (longitudinal studies). The meta-analysis showed a significant reduction in both CD3+ lymphocytes (SMD −0.85 [95% CI −1.23; −0.47]) and CD68+ macrophages (sublining, sl) (SMD −0.74 [−1.16; −0.32]) in synovial biopsies from patients treated for 4–12 weeks with bDMARDs. Reduction in CD3+ mostly correlated with clinical response. Despite heterogeneity among the biomarkers evaluated, the reduction in CD3+/CD68+sl cells during the first 3 months of treatment with TNF inhibitors represents the most consistent variation reported in the literature.

Permeability transition pore (PTP) molecular composition and activity modulation have been a matter of research for several years, especially due to their importance in ischemia reperfusion injury (IRI). Notably, c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and as a target for cardioprotection. Oligomycin A is a well-known Csub interactor that has been chemically modified in-depth for proposed new pharmacological approaches against cardiac reperfusion injury. Indeed, by taking advantage of its scaffold and through focused chemical improvements, innovative Csub-dependent PTP inhibitors (1,3,8-Triazaspiro[4.5]decane) have been synthetized in the past. Interestingly, four critical amino acids have been found to be involved in Oligomycin A-Csub binding in yeast. However, their position on the human sequence is unknown, as is their function in PTP inhibition. The aims of this study are to (i) identify for the first time the topologically equivalent residues in the human Csub sequence; (ii) provide their in vitro validation in Oligomycin A-mediated PTP inhibition and (iii) understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane small molecules, as Oligomycin A derivatives, in order to provide insights into Csub interactions. Notably, in this study we demonstrated that 1,3,8-Triazaspiro[4.5]decane derivatives inhibit permeability transition pores through a FO-ATP synthase c subunit Glu119-independent mechanism that prevents Oligomycin A-related side effects.

Intracellular calcium signaling is a universal language source shared by the most part of biological entities inside cells that, all together, give rise to physiological and functional anatomical units, the organ. Although preferentially recognized as signaling between cell life and death processes, in the heart it assumes additional relevance considered the importance of calcium cycling coupled to ATP consumption in excitation-contraction coupling. The concerted action of a plethora of exchangers, channels and pumps inward and outward calcium fluxes where needed, to convert energy and electric impulses in muscle contraction. All this without realizing it, thousands of times, every day. An improper function of those proteins (i.e., variation in expression, mutations onset, dysregulated channeling, differential protein-protein interactions) being part of this signaling network triggers a short circuit with severe acute and chronic pathological consequences reported as arrhythmias, cardiac remodeling, heart failure, reperfusion injury and cardiomyopathies. By acting with chemical, peptide-based and pharmacological modulators of these players, a correction of calcium homeostasis can be achieved accompanied by an amelioration of clinical symptoms.This review will focus on all those defects in calcium homeostasis which occur in the most common cardiac diseases, including myocardial infarction, arrhythmia, hypertrophy, heart failure and cardiomyopathies. This part will be introduced by the state of the art on the proteins involved in calcium homeostasis in cardiomyocytes and followed by the therapeutic treatments that to date, are able to target them and to revert the pathological phenotype.

Abstract Tissue engineering‐based bone graft is an emerging viable treatment modality to repair and regenerate tissues damaged as a result of diseases or injuries. The structure and composition of scaffolds should modulate the classical osteogenic pathways in human stem cells. The osteoinductivity properties of the hydroxylapatite‐collagen hybrid scaffold named Coll/Pro Osteon 200 were investigated in an in vitro model of human adipose mesenchymal stem cells (hASCs), whereas the clinical evaluation was carried out in maxillofacial patients. Differentially expressed genes (DEGs) induced by the scaffold were analyzed using the Osteogenesis RT2 PCR Array. The osteoinductivity potential of the scaffold was also investigated by studying the alkaline phosphatase (ALP) activity, matrix mineralization, osteocalcin (OCN), and CLEC3B expression protein. Fifty patients who underwent zygomatic augmentation and bimaxillary osteotomy were evaluated clinically, radiologically, and histologically during a 3‐year follow‐up. Among DEGs, osteogenesis‐related genes, including BMP1/2, ALP, BGLAP, SP7, RUNX2, SPP1, and EGFR, which play important roles in osteogenesis, were found to be upregulated. The genes to cartilage condensation SOX9, BMPR1B, and osteoclast cells TNFSF11 were detected upregulated at every time point of the investigation. This scaffold has a high osteoinductivity revealed by the matrix mineralization, ALP activity, OCN, and CLEC3B expression proteins. Clinical evaluation evidences that the biomaterial promotes bone regrowth. Histological results of biopsy specimens from patients showed prominent ossification. Experimental data using the Coll/Pro Osteon 200 indicate that clinical evaluation of bone regrowth in patients, after scaffold implantation, was supported by DEGs implicated in skeletal development as shown in “in vitro” experiments with hASCs.

Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.

Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically “predictive”: the expected response is based on stratification according to clinical, imaging, and laboratory data, with a “heuristic” approach based on “trial and error”. Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially “broad-spectrum” mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of “refractory to a treatment” patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.

Abstract Background An alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS). Objective To search the level of autophagy-related 5 (ATG5) and Parkin proteins, as markers of autophagy and mitophagy respectively, and lactate in a cohort of MS patients. Methods Cerebrospinal fluid (CSF) and serum samples from 60 MS patients were analyzed: 30 with magnetic resonance imaging (MRI) evidence of disease activity, gadolinium (Gd)-based contrast agent positive (Gd+), and 30 without MRI evidence of disease activity (Gd−). ATG5, Parkin, and lactate were measured using commercially available products. Results and conclusions Serum levels of ATG5, Parkin, and lactate were more elevated in Gd+ than in Gd− MS patients (p

Autophagy is a highly conserved dynamic process by which cells deliver their contents to lysosomes for degradation, thus ensuring cell homeostasis. In response to environmental stress, the induction of autophagy is crucial for cell survival. The dysregulation of this degradative process has been implicated in a wide range of pathologies, including lung diseases, representing a relevant potential target with significant clinical outcomes. During lung disease progression and infections, autophagy may exert both protective and harmful effects on cells. In this review, we will explore the implications of autophagy and its selective forms in several lung infections, such as SARS-CoV-2, Respiratory Syncytial Virus (RSV) and Mycobacterium tuberculosis (Mtb) infections, and different lung diseases such as Cystic Fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), and Malignant Mesothelioma (MM).

Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer arising from the mesothelial cells lining the pleural cavity. MPM is characterized by a silent clinical progression and a highly resistance to conventional chemo/radio-therapies. MPM patients die in a few months/years from diagnosis. Notch signaling is a well-conserved cell communication system, which regulates many biological processes. In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM. Metformin is the first-line drug used to treat type 2 diabetes mellitus. Metformin is proven to be an effective antitumor drug in preclinical models of different types of cancer. To date, clinical efficacy is being studied in many clinical trials. In this study, the anti-proliferative effect of metformin on MPM cells and the putative involvement of Notch1 as a mediator of metformin activities, were investigated. MPM cells showed high levels of Notch1 activation compared to normal pleural mesothelial cells. Furthermore, metformin treatment hampered MPM cell proliferation and enhanced the apoptotic process, accompanied by decreased Notch1 activation.

Cystic fibrosis (CF) is a genetic disease associated to mutations in the cystic fibrosis transmembrane conductance regulator gene, which results in the alteration of biological fluid and electrolyte homeostasis. The characteristic pathological manifestation is represented by exaggerated proinflammatory response in lung of CF patients, driven by recurrent infections and worsen by hypersecretion of proinflammatory mediators and progressive tissue destruction. Treating inflammation remains a priority in CF. However, current anti-inflammatory treatments, including non-steroidal agents, are poorly effective and present dramatic side effects in CF patients. Different studies suggest an intimate relationship between mitochondria and CF lung disease, supporting the hypothesis that a decline in mitochondrial function endorses the development of the hyperinflammatory phenotype observed in CF lung. This allowed the implementation of a new concept: the “mito-inflammation,” a compartmentalization of inflammatory process, related to the role of mitochondria in engage and sustain the inflammatory responses, resulting a druggable target to counteract the amplification of inflammatory signals in CF. Here, we will offer an overview of the contribution of mitochondria in the pathogenesis of CF lung disease, delving into mitochondrial quality control responses, which concur significantly to exacerbation of CF lung inflammatory responses. Finally, we will discuss the new therapeutic avenues that aim to target the mito-inflammation, an alternative therapeutic advantage for mitochondrial quality control that improves CF patient’s inflammatory state.

Cardiovascular diseases (CVDs) and cancer continue to be the primary cause of mortality worldwide and their pathomechanisms are a complex and multifactorial process. Insufficient oxygen availability (hypoxia) plays critical roles in the pathogenesis of both CVDs and cancer diseases, and hypoxia-inducible factor 1 (HIF-1), the main sensor of hypoxia, acts as a central regulator of multiple target genes in the human body. Accumulating evidence demonstrates that mitochondria are the major target of hypoxic injury, the most common source of reactive oxygen species during hypoxia and key elements for inflammation regulation during the development of both CVDs and cancer. Taken together, observations propose that hypoxia, mitochondrial abnormality, oxidative stress, inflammation in CVDs, and cancer are closely linked. Based upon these facts, this review aims to deeply discuss these intimate relationships and to summarize current significant findings corroborating the molecular mechanisms and potential therapies involved in hypoxia and mitochondrial dysfunction in CVDs and cancer.

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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.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.

A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

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.

Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation.

Abnormal levels of pyruvate and lactate were reported in multiple sclerosis (MS). We studied the response of markers of mitochondrial function to rehabilitation in relation to type, intensity and endurance performance in severely disabled MS patients. Forty-six progressive MS patients were randomized to receive 12 walking sessions of robot-assisted gait training (RAGT, n = 23) or conventional overground therapy (CT, n = 23). Ten healthy subjects were also studied. Blood samples were collected to determine lactate, pyruvate, and glutathione levels and lactate/pyruvate ratio pre–post rehabilitation. In vivo muscle metabolism and endurance walking capacity were assessed by resting muscle oxygen consumption (rmVO2) using near-infrared spectroscopy and by six-minute walking distance (6MWD), respectively. The levels of mitochondrial biomarkers and rmVO2, altered at baseline with respect to healthy subjects, improved after rehabilitation in the whole population. In the two groups, an enhanced response was observed after RAGT compared to CT for lactate (p = 0.012), glutathione (p = 0.08) and rmVO2 (p = 0.07). Metabolic biomarkers and 6MWD improvements were exclusively correlated with a training speed markedly below individual gait speed. In severely disabled MS patients, rehabilitation rebalanced altered serum metabolic and muscle parameters, with RAGT being more effective than CT. A determinable slow training speed was associated with better metabolic and functional recovery. Trial Registration: ClinicalTrials.gov NCT02421731.

Calcific aortic stenosis is a disorder that impacts the physiology of heart valves. Fibrocalcific events progress in conjunction with thickening of the valve leaflets. Over the years, these events promote stenosis and obstruction of blood flow. Known and common risk factors are congenital defects, aging and metabolic syndromes linked to high plasma levels of lipoproteins. Inflammation and oxidative stress are the main molecular mediators of the evolution of aortic stenosis in patients and these mediators regulate both the degradation and remodeling processes. Mitochondrial dysfunction and dysregulation of autophagy also contribute to the disease. A better understanding of these cellular impairments might help to develop new ways to treat patients since, at the moment, there is no effective medical treatment to diminish neither the advancement of valve stenosis nor the left ventricular function impairments, and the current approaches are surgical treatment or transcatheter aortic valve replacement with prosthesis.

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.

Mitochondrial Lon protease (LonP1) is a multi-function enzyme that regulates mitochondrial functions in several human malignancies, including colorectal cancer (CRC). The mechanism(s) by which LonP1 contributes to colorectal carcinogenesis is not fully understood. We found that silencing LonP1 leads to severe mitochondrial impairment and apoptosis in colon cancer cells. Here, we investigate the role of LonP1 in mitochondrial functions, metabolism, and epithelial–mesenchymal transition (EMT) in colon tumor cells and in metastasis. LonP1 was almost absent in normal mucosa, gradually increased from aberrant crypt foci to adenoma, and was most abundant in CRC. Moreover, LonP1 was preferentially upregulated in colorectal samples with mutated p53 or nuclear β-catenin, and its overexpression led to increased levels of β-catenin and decreased levels of E-cadherin, key proteins in EMT, in vitro. LonP1 upregulation also induced opposite changes in oxidative phosphorylation, glycolysis, and pentose pathway in SW480 primary colon tumor cells when compared to SW620 metastatic colon cancer cells. In conclusion, basal LonP1 expression is essential for normal mitochondrial function, and increased LonP1 levels in SW480 and SW620 cells induce a metabolic shift toward glycolysis, leading to EMT.

Abstract Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3–0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss‐of‐function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss‐of‐function activates the mTOR‐ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole‐cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2‐silenced human endothelial cells and in both cells and tissues from an endothelial‐specific CCM3‐knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial‐to‐mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.