Giampaolo Morciano - Academia.edu (original) (raw)
Papers by Giampaolo Morciano
Life
The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole ... more The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole body through rhythmic and vigorous contractions. Heart function relies on a delicate balance between continuous energy consumption and generation that changes from birth to adulthood and depends on a very efficient oxidative metabolism and the ability to adapt to different conditions. In recent years, mitochondrial dysfunctions were recognized as the hallmark of the onset and development of manifold heart diseases (HDs), including heart failure (HF). HF is a severe condition for which there is currently no cure. In this condition, the failing heart is characterized by a disequilibrium in mitochondrial bioenergetics, which compromises the basal functions and includes the loss of oxygen and substrate availability, an altered metabolism, and inefficient energy production and utilization. This review concisely summarizes the bioenergetics and some other mitochondrial features in the heart wi...
Biomolecules
Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner m... more 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 ad...
International Journal of Molecular Sciences
Calcific aortic stenosis is a disorder that impacts the physiology of heart valves. Fibrocalcific... more 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 val...
Cardiovascular Research
Aims In the last 15 years, some observations tried to shed light on the dysregulation of the cell... more Aims In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS. Methods and results This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the p...
Journal of Clinical Medicine
Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in differen... more Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in different types of cancers. Their level can be potentially associated with oncogenic processes. We analyzed samples of pediatric brain tumors reflecting different groups such as choroid plexus tumors, diffuse astrocytic and oligodendroglial tumors, embryonal tumors, ependymal tumors, and other astrocytic tumors as well as tumor malignancy grade, in order to characterize the expression profile of Ras, TrkB, and three isoforms of ShcA, namely, p66Shc, p52Shc, and p46Shc proteins. The main aim of our study was to evaluate the potential correlation between the type of pediatric brain tumors, tumor malignancy grade, and the expression patterns of the investigated proteins.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Scientific Reports
Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1... more Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology. Alzheimer Disease (AD) is the most common form of dementia, mainly attributed to altered processing and deposition of extracellular Aβ plaques and intracellular neurofibrillary tangles in the brain 1. Current understanding of AD pathophysiology indicates impairment of several cellular processes such as lipid metabolism, mitochondrial function and autophagy, leading eventually to cellular stress and death. A multifactorial model for AD proposes a cellular phase in which Amyloid beta (Aβ) pathology drives Tau hyperphosphorylation inducing cellular damage 2. Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2) autosomal dominant mutations are causative of familial AD (FAD) 3. FAD is characterized by its severity and earlier disease onset, together with severe brain atrophy indicating increased neuronal death 4. Presenilins are the catalytic component of the γ-secretase complex, playing a role in Aβ generation. The pathological severity of FAD suggests a direct neurodegenerative role of PS1 mutations, whether by increased production of toxic Aβ or by other mechanisms 5. Nevertheless, PS1 has also been related to other cellular functions, such as protein trafficking, Wnt/β-catenin signaling, apoptosis and the disruption of calcium homeostasis 6-8. Accordingly, PS1 mutations have been associated to increased cellular stress or death responses such as endoplasmic reticulum (ER) stress 9 , oxidative stress 10,11 , autophagy 12 , and apoptosis 13. Abnormal calcium homeostasis and its pathological role (calcium overload) in AD have attracted attention during recent years. Calcium signaling is involved in different pathways, being essential for synaptic mechanisms, protein folding processes, cell survival and death, among many others 14. Regarding
Journal of Clinical Medicine
Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown tha... more Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular diseas...
Cell Death & Disease
Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in da... more Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care. Facts • Melatonin is a ubiquitous molecule with natural and powerful antioxidant proprieties and administration of exogenous melatonin is safe • Melatonin exerts anti-inflammatory effects mainly by inhibiting inflammasome activation • Melatonin exerts its antiapoptotic activities mainly by blocking caspase 3 cleavage and mPTP opening • "Oxygen radical diseases of neonatology" refers to the oxidative stress that has a leading role in the pathogenesis of neonatal morbidities and pathologic conditions
Advances in Interventional Cardiology
Cell death & disease, Jan 28, 2018
Inter-organellar communication often takes the form of Ca signals. These Ca signals originate fro... more Inter-organellar communication often takes the form of Ca signals. These Ca signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca signals are the mitochondria. ER-mitochondrial Ca transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca uptake. In the mitochondria, the Ca signal is decoded differentially depending on its spatiotemporal characteristics. While Ca oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca overload results in apoptosis. Many chemotherapeutics depend on efficient ER-mitochondrial Ca signaling to exert their function. However, several oncogenes and tumor suppressors present in t...
Cell death and differentiation, Jan 24, 2018
STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcripti... more STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca release by interacting with the Ca channel IP3R3 and facilitating its degradation. The release of Ca is of paramount importance for life/death cell decisions, as excessive Ca causes mitochondrial Ca overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca release and sensitivity to apoptos...
![Research paper thumbnail of {"__content__"=>"Constitutive IP signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP receptor disruptor BIRD-2.", "sub"=>[{"__content__"=>"3"}, {"__content__"=>"3"}]}](https://attachments.academia-assets.com/71527130/thumbnails/1.jpg)
](Cell death and differentiation, Jan 13, 2018
Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cel... more Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP) receptor (IPR)-mediated Ca-signaling. A peptide tool (Bcl-2/IPR Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IPRs by targeting Bcl-2's BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IPR2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IPR2-expression levels, but also on constitutive IP signaling, downstream of the tonically active B-cell receptor. The basal Ca level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP production. This constitutive IP signaling fulfilled a pro-survival role, since inhibition of phosph...
Neoplasia (New York, N.Y.), 2018
Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcel... more 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 can...
Journal of medicinal chemistry, Jan 23, 2018
Recent cardiology research studies have reported the role, function, and structure of the mitocho... more Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F/F-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels....
International review of cell and molecular biology, 2018
Aging has been linked to several degenerative processes that, through the accumulation of molecul... more Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of sever...
Advances in experimental medicine and biology, 2017
Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatmen... more Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatment of choice for reducing ischemic injury and limiting infarct size (IS) in patients with ST-segment elevation MI (STEMI) is timely and effective myocardial reperfusion via primary percutaneous coronary intervention (PCI). However, myocardial reperfusion itself may induce further cardiomyocyte death, a phenomenon known as reperfusion injury (RI). The opening of a large pore in the mitochondrial membrane, namely, the mitochondrial permeability transition pore (mPTP), is widely recognized as the final step of RI and is responsible for mitochondrial and cardiomyocyte death. Although myocardial reperfusion interventions continue to improve, there remain no effective therapies for preventing RI due to incomplete knowledge regarding RI components and mechanisms and to premature translations of findings from animals to humans. In the last year, increasing amounts of data describing mPTP componen...
Life
The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole ... more The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole body through rhythmic and vigorous contractions. Heart function relies on a delicate balance between continuous energy consumption and generation that changes from birth to adulthood and depends on a very efficient oxidative metabolism and the ability to adapt to different conditions. In recent years, mitochondrial dysfunctions were recognized as the hallmark of the onset and development of manifold heart diseases (HDs), including heart failure (HF). HF is a severe condition for which there is currently no cure. In this condition, the failing heart is characterized by a disequilibrium in mitochondrial bioenergetics, which compromises the basal functions and includes the loss of oxygen and substrate availability, an altered metabolism, and inefficient energy production and utilization. This review concisely summarizes the bioenergetics and some other mitochondrial features in the heart wi...
Biomolecules
Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner m... more 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 ad...
International Journal of Molecular Sciences
Calcific aortic stenosis is a disorder that impacts the physiology of heart valves. Fibrocalcific... more 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 val...
Cardiovascular Research
Aims In the last 15 years, some observations tried to shed light on the dysregulation of the cell... more Aims In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS. Methods and results This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the p...
Journal of Clinical Medicine
Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in differen... more Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in different types of cancers. Their level can be potentially associated with oncogenic processes. We analyzed samples of pediatric brain tumors reflecting different groups such as choroid plexus tumors, diffuse astrocytic and oligodendroglial tumors, embryonal tumors, ependymal tumors, and other astrocytic tumors as well as tumor malignancy grade, in order to characterize the expression profile of Ras, TrkB, and three isoforms of ShcA, namely, p66Shc, p52Shc, and p46Shc proteins. The main aim of our study was to evaluate the potential correlation between the type of pediatric brain tumors, tumor malignancy grade, and the expression patterns of the investigated proteins.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Scientific Reports
Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1... more Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer's disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma N2a cells. We examined early signs of stress in different conditions: endoplasmic reticulum (ER) stress, calcium overload, oxidative stress, and Aβ 1-42 oligomers toxicity. Additionally, we induced autophagy via serum starvation. PS1 mutations did not have an effect in ER stress but PS1E280A mutation affected autophagy. PS1 overexpression influenced calcium homeostasis and generated mitochondrial calcium overload modifying mitochondrial function. However, the opening of the mitochondrial permeability transition pore (MPTP) was affected in PS1 mutants, being accelerated in PS1E280A and inhibited in PS1Δ9 cells. Altered autophagy in PS1E280A cells was neither modified by inhibition of γ-secretase, nor by ER calcium retention. MPTP opening was directly regulated by γ-secretase inhibitors independent on organelle calcium modulation, suggesting a novel direct role for PS1 and γ-secretase in mitochondrial stress. We identified intrinsic cellular vulnerability to stress in PS1 mutants associated simultaneously with both, autophagic and mitochondrial function, independent of Aβ pathology. Alzheimer Disease (AD) is the most common form of dementia, mainly attributed to altered processing and deposition of extracellular Aβ plaques and intracellular neurofibrillary tangles in the brain 1. Current understanding of AD pathophysiology indicates impairment of several cellular processes such as lipid metabolism, mitochondrial function and autophagy, leading eventually to cellular stress and death. A multifactorial model for AD proposes a cellular phase in which Amyloid beta (Aβ) pathology drives Tau hyperphosphorylation inducing cellular damage 2. Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2) autosomal dominant mutations are causative of familial AD (FAD) 3. FAD is characterized by its severity and earlier disease onset, together with severe brain atrophy indicating increased neuronal death 4. Presenilins are the catalytic component of the γ-secretase complex, playing a role in Aβ generation. The pathological severity of FAD suggests a direct neurodegenerative role of PS1 mutations, whether by increased production of toxic Aβ or by other mechanisms 5. Nevertheless, PS1 has also been related to other cellular functions, such as protein trafficking, Wnt/β-catenin signaling, apoptosis and the disruption of calcium homeostasis 6-8. Accordingly, PS1 mutations have been associated to increased cellular stress or death responses such as endoplasmic reticulum (ER) stress 9 , oxidative stress 10,11 , autophagy 12 , and apoptosis 13. Abnormal calcium homeostasis and its pathological role (calcium overload) in AD have attracted attention during recent years. Calcium signaling is involved in different pathways, being essential for synaptic mechanisms, protein folding processes, cell survival and death, among many others 14. Regarding
Journal of Clinical Medicine
Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown tha... more Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular diseas...
Cell Death & Disease
Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in da... more Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care. Facts • Melatonin is a ubiquitous molecule with natural and powerful antioxidant proprieties and administration of exogenous melatonin is safe • Melatonin exerts anti-inflammatory effects mainly by inhibiting inflammasome activation • Melatonin exerts its antiapoptotic activities mainly by blocking caspase 3 cleavage and mPTP opening • "Oxygen radical diseases of neonatology" refers to the oxidative stress that has a leading role in the pathogenesis of neonatal morbidities and pathologic conditions
Advances in Interventional Cardiology
Cell death & disease, Jan 28, 2018
Inter-organellar communication often takes the form of Ca signals. These Ca signals originate fro... more Inter-organellar communication often takes the form of Ca signals. These Ca signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca signals are the mitochondria. ER-mitochondrial Ca transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca uptake. In the mitochondria, the Ca signal is decoded differentially depending on its spatiotemporal characteristics. While Ca oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca overload results in apoptosis. Many chemotherapeutics depend on efficient ER-mitochondrial Ca signaling to exert their function. However, several oncogenes and tumor suppressors present in t...
Cell death and differentiation, Jan 24, 2018
STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcripti... more STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca release by interacting with the Ca channel IP3R3 and facilitating its degradation. The release of Ca is of paramount importance for life/death cell decisions, as excessive Ca causes mitochondrial Ca overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca release and sensitivity to apoptos...
Cell death and differentiation, Jan 13, 2018
Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cel... more Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP) receptor (IPR)-mediated Ca-signaling. A peptide tool (Bcl-2/IPR Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IPRs by targeting Bcl-2's BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IPR2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IPR2-expression levels, but also on constitutive IP signaling, downstream of the tonically active B-cell receptor. The basal Ca level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP production. This constitutive IP signaling fulfilled a pro-survival role, since inhibition of phosph...
Neoplasia (New York, N.Y.), 2018
Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcel... more 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 can...
Journal of medicinal chemistry, Jan 23, 2018
Recent cardiology research studies have reported the role, function, and structure of the mitocho... more Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F/F-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels....
International review of cell and molecular biology, 2018
Aging has been linked to several degenerative processes that, through the accumulation of molecul... more Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of sever...
Advances in experimental medicine and biology, 2017
Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatmen... more Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatment of choice for reducing ischemic injury and limiting infarct size (IS) in patients with ST-segment elevation MI (STEMI) is timely and effective myocardial reperfusion via primary percutaneous coronary intervention (PCI). However, myocardial reperfusion itself may induce further cardiomyocyte death, a phenomenon known as reperfusion injury (RI). The opening of a large pore in the mitochondrial membrane, namely, the mitochondrial permeability transition pore (mPTP), is widely recognized as the final step of RI and is responsible for mitochondrial and cardiomyocyte death. Although myocardial reperfusion interventions continue to improve, there remain no effective therapies for preventing RI due to incomplete knowledge regarding RI components and mechanisms and to premature translations of findings from animals to humans. In the last year, increasing amounts of data describing mPTP componen...