Mitophagy in Cardiovascular Diseases

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 disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes

The Role of Hypoxic Inducible Factor-1 Alpha Subunit in Mitochondrial Function in Ischemic Heart Disease

La cardiopatia ischemica è il tipo più comune di disturbo cardiaco e rappresenta una delle principali cause di mortalità in tutto il mondo. Recentemente, l'Hypoxia-inducible factor-1 alpha (HIF-1α) ha attirato molta attenzione in molti campi di ricerca; è stata delineata la sua importanza come un fattore di trascrizione principale, attivato durante l'ipossia che agisce da modulatore chiave di diversi geni target nel corpo umano, tra cui apoptosi / sopravvivenza e riprogrammazione metabolica in risposta all'ipossia 1,2. I mitocondri sono la centrale elettrica del consumo di ossigeno, significativamente abbondanti nel cuore, e sono emersi come un importante regolatore della salute e della malattia cardiovascolare. Diversi processi cellulari sono dedicati al mantenimento della funzione mitocondriale nell'omeostasi cardiovascolare. Nel presente studio, abbiamo voluto indagare il ruolo di HIF-1α sull'omeostasi mitocondriale, in particolare il suo contatto con il reticolo endoplasmatico durante l'ipossia indotta dalla deferoxamina in cardiomiociti umani. Sono stati studiati altri diversi eventi cellulari in risposta all'ipossia, come la morte cellulare (apoptosi e necrosi), l'omeostasi del calcio, l'autofagia/mitofagia. Inoltre, abbiamo chiarito l'effetto di HIF-1 nella regolazione del poro di transizione della permeabilità mitocondriale (mPTP) in risposta all'ipossia. Pertanto, abbiamo voluto esaminare la localizzazione di HIF-1α, dopo la sua stabilizzazione, nel nostro modello cellulare e svelare i suoi nuovi possibili ruoli efficaci durante l'ipossia. Abbiamo anche confrontato l'effetto di HIF-1α s ull'omeostasi mitocondriale nei cardiomiociti neonatali e nei fibroblasti cardiaci in risposta all'ipossia. La prima parte del lavoro ha permesso di descrivere gli effetti di HIF-1α in risposta all'ipossia mediata da DFO in cardiomiociti umani. La scoperta principale di questo lavoro è che HIF-1α gioca un doppio ruolo nei cardiomiociti umani durante l'ipossia indotta da DFO, influenzando la funzione mitocondriale e le MAMs successivamente influenzando vari processi cellulari fondamentali, l'autofagia/mitofagia, la morte cellulare, l'omeostasi del calcio in modo dose e tempo dipendente. Nella seconda parte del nostro lavoro abbiamo identificato per la prima volta una nuova localizzazione di HIF-1α nei cardiomiociti umani in risposta all'ipossia. Inoltre, lo studio in corso sull'attività di trascrizione di HIF-1α ha mostrato per la prima volta due copie predette di HRE putative che comprendono Sequenze consenso del gene ITPR3. Inoltre, in un altro modello cellulare di cardiomiociti neonatali (RNC) e di fibroblasti cardiaci (RCF), l'ipossia indotta da DFO ha colpito entrambe le cellule in modo diverso, in cui RCF erano più resistenti allo stress ossidativo mitocondriale indotto dall'ipossia rispetto alle RNC. Infatti, il potenziale di membrana mitocondriale le RNC è stato depolarizzato al momento dell'induzione dell'ipossia. In conclusione, questi risultati suggeriscono nuove Informazioni sul ruolo della proteina hallmark HIF-1α nelle cellule cardiache durante l'ipossia, sottolineando le relazioni tra HIF-1α /mitocondri e reticolo endoplasmatico, concentrandosi sull'effetto di cardioprotezione di HIF-1α.Ischemic heart disease is the most common type of heart disorder and represents a major cause of mortality worldwide. Recently, Hypoxia-inducible factor-1 alpha (HIF-1α) has drawn much attention in many research fields, have outlined its importance as a master transcription factor activated during hypoxia, and acts as a key modulator of diverse target genes in the human body including, apoptosis/ survival, metabolic reprogramming in response to hypoxia 1,2. Mitochondria are the powerhouse of oxygen consumption, significantly abundant in the heart, and have emerged as an important regulator of cardiovascular health and disease. Several cellular processes are dedicated to maintaining mitochondrial function in cardiovascular homeostasis. In the present study, we aimed to investigate the role of HIF-1α on mitochondrial homeostasis, especially its contact with the endoplasmic reticulum during hypoxia-induced by deferoxamine in human cardiomyocytes. Further different cellular events in response to hypoxia were studied, such as cell death (apoptosis and necrosis), calcium homeostasis, autophagy/mitophagy. Additionally, we elucidated the effect of HIF-1 in regulating the mitochondrial permeability transition pore (mPTP) in response to hypoxia. Therefore, we aimed to examine the localization of HIF-1α after its stabilization in our cell model and unveil its new possible effective roles during hypoxia. We also compared the effect of HIF-1α on the mitochondrial homeostasis in neonatal cardiomyocytes and cardiac fibroblasts in response to hypoxia. The first part of the work performed experiments allowed the description of the effects of HIF-1α in response to DFO-mediated hypoxia in human cardiomyocytes. The main finding of this work is that HIF-1α plays a dual role in human cardiomyocytes during DFO induced-hypoxia, affecting the mitochondrial function and MAMs subsequently affecting various fundamental cellular processes, autophagy/mitophagy, cell death, calcium homeostasis in a dose and time-dependent manner. In the second part of our work, we identified for the first time a new localization of HIF-1α in human cardiomyocytes in response to hypoxia. Furthermore, the ongoing study on HIF-1α transcription activity showed for the first time two predicted copies of putative HRE encompassing consensus sequences of ITPR3 gene. Additionally, in other cell model neonatal cardiomyocytes (RNC) and cardiac fibroblasts (RCF), hypoxia-induced by DFO affected both cells differently, in which RCF were more resistant to hypoxia-induced mitochondrial oxidative stress compared with RNC. Indeed, the mitochondrial membrane potential of RNC was depolarized at an increased time of hypoxia induction. Conclusively, these findings suggest new insights on the role of the hallmark protein HIF-1α in cardiac cells during hypoxia, emphasizing the relationships between HIF-1α /mitochondria and endoplasmic reticulum, focusing on the cardioprotection effect of HIF-1α

Mitochondrial Oxidative Stress and "Mito-Inflammation": Actors in the Diseases

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

Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases

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

Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases

The most common alterations affecting mitochondria, and associated with cardiac pathological conditions, implicate a long list of defects. They include impairments of the mitochondrial electron transport chain activity, which is a crucial element for energy formation, and that determines the depletion of ATP generation and supply to metabolic switches, enhanced ROS generation, inflammation, as well as the dysregulation of the intracellular calcium homeostasis. All these signatures significantly concur in the impairment of cardiac electrical characteristics, loss of myocyte contractility and cardiomyocyte damage found in cardiac diseases. Mitochondrial dynamics, one of the quality control mechanisms at the basis of mitochondrial fitness, also result in being dysregulated, but the use of this knowledge for translational and therapeutic purposes is still in its infancy. In this review we tried to understand why this is, by summarizing methods, current opinions and molecular details underlying mitochondrial dynamics in cardiac diseases

Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases

The most common alterations affecting mitochondria, and associated with cardiac pathological conditions, implicate a long list of defects. They include impairments of the mitochondrial electron transport chain activity, which is a crucial element for energy formation, and that determines the depletion of ATP generation and supply to metabolic switches, enhanced ROS generation, inflammation, as well as the dysregulation of the intracellular calcium homeostasis. All these signatures significantly concur in the impairment of cardiac electrical characteristics, loss of myocyte contractility and cardiomyocyte damage found in cardiac diseases. Mitochondrial dynamics, one of the quality control mechanisms at the basis of mitochondrial fitness, also result in being dysregulated, but the use of this knowledge for translational and therapeutic purposes is still in its infancy. In this review we tried to understand why this is, by summarizing methods, current opinions and molecular details underlying mitochondrial dynamics in cardiac diseases

Some Insights into the Regulation of Cardiac Physiology and Pathology by the Hippo Pathway

The heart is one of the most fascinating organs in living beings. It beats up to 100,000 times a day throughout the lifespan, without resting. The heart undergoes profound anatomical, biochemical, and functional changes during life, from hypoxemic fetal stages to a completely differentiated four-chambered cardiac muscle. In the middle, many biological events occur after and intersect with each other to regulate development, organ size, and, in some cases, regeneration. Several studies have defined the essential roles of the Hippo pathway in heart physiology through the regulation of apoptosis, autophagy, cell proliferation, and differentiation. This molecular route is composed of multiple components, some of which were recently discovered, and is highly interconnected with multiple known prosurvival pathways. The Hippo cascade is evolutionarily conserved among species, and in addition to its regulatory roles, it is involved in disease by drastically changing the heart phenotype and its function when its components are mutated, absent, or constitutively activated. In this review, we report some insights into the regulation of cardiac physiology and pathology by the Hippo pathway

Some Insights into the Regulation of Cardiac Physiology and Pathology by the Hippo Pathway

The heart is one of the most fascinating organs in living beings. It beats up to 100,000 times a day throughout the lifespan, without resting. The heart undergoes profound anatomical, biochemical, and functional changes during life, from hypoxemic fetal stages to a completely differentiated four-chambered cardiac muscle. In the middle, many biological events occur after and intersect with each other to regulate development, organ size, and, in some cases, regeneration. Several studies have defined the essential roles of the Hippo pathway in heart physiology through the regulation of apoptosis, autophagy, cell proliferation, and differentiation. This molecular route is composed of multiple components, some of which were recently discovered, and is highly interconnected with multiple known prosurvival pathways. The Hippo cascade is evolutionarily conserved among species, and in addition to its regulatory roles, it is involved in disease by drastically changing the heart phenotype and its function when its components are mutated, absent, or constitutively activated. In this review, we report some insights into the regulation of cardiac physiology and pathology by the Hippo pathway

Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

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

The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches

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