-
1.
The Role of Mitochondrial Quality Control in Cardiac Ischemia/Reperfusion Injury.
Huang, J, Li, R, Wang, C
Oxidative medicine and cellular longevity. 2021;:5543452
Abstract
A healthy mitochondrial network produces a large amount of ATP and biosynthetic intermediates to provide sufficient energy for myocardium and maintain normal cell metabolism. Mitochondria form a dynamic and interconnected network involved in various cellular metabolic signaling pathways. As mitochondria are damaged, controlling mitochondrial quantity and quality is activated by changing their morphology and tube network structure, mitophagy, and biogenesis to replenish a healthy mitochondrial network to preserve cell function. There is no doubt that mitochondrial dysfunction has become a key factor in many diseases. Ischemia/reperfusion (IR) injury is a pathological manifestation of various heart diseases. Cardiac ischemia causes temporary tissue and organelle damage. Although reperfusion is essential to compensate for nutrient deficiency, blood flow restoration inconsequently further kills the previously ischemic cardiomyocytes. To date, dysfunctional mitochondria and disturbed mitochondrial quality control have been identified as critical IR injury mechanisms. Many researchers have detected abnormal mitochondrial morphology and mitophagy, as well as aberrant levels and activity of mitochondrial biogenesis factors in the IR injury model. Although mitochondrial damage is well-known in myocardial IR injury, the causal relationship between abnormal mitochondrial quality control and IR injury has not been established. This review briefly describes the molecular mechanisms of mitochondrial quality control, summarizes our current understanding of the complex role of mitochondrial quality control in IR injury, and finally speculates on the possibility of targeted control of mitochondria and the methods available to mitigate IR injury.
-
2.
Is Cardiac Diastolic Dysfunction a Part of Post-Menopausal Syndrome?
Maslov, PZ, Kim, JK, Argulian, E, Ahmadi, A, Narula, N, Singh, M, Bax, J, Narula, J
JACC. Heart failure. 2019;(3):192-203
Abstract
Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.
-
3.
Cardiomyocyte mitochondrial dysfunction in diabetes and its contribution in cardiac arrhythmogenesis.
El Hadi, H, Vettor, R, Rossato, M
Mitochondrion. 2019;:6-14
Abstract
Cardiovascular disease is the leading cause of diabetes-related morbidity and mortality. It is widely accepted that heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Mitochondria are the center of fatty acid (FA) and glucose metabolism and thus are likely to be impacted by impaired metabolism associated with diabetes. Although the cause of this increased heart failure risk is multifactorial, increasing evidence points toward a crucial role for cardiomyocyte mitochondria dysfunction. Altered energy metabolism, defects in mitochondrial dynamics, increased oxidative stress, impaired calcium (Ca2+) handling and mitochondria-induced cell death are observed in mitochondria of diabetic myocardium. In addition, mitochondrial dysfunction appears to contribute substantially to the origin of arrhythmias in diabetic hearts. The current review will describe these mitochondrial abnormalities in cardiomyocytes attempting to provide an overview of underlying mechanisms. Finally, we briefly discuss the potential link between mitochondrial malfunction and arrhythmogenesis.
-
4.
SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca2+ has a lot to say.
De la Fuente, S, Sheu, SS
Archives of biochemistry and biophysics. 2019;:259-268
-
-
Free full text
-
Abstract
In adult cardiomyocytes, T-tubules, junctional sarcoplasmic reticulum (jSR), and mitochondria juxtapose each other and form a unique and highly repetitive functional structure along the cell. The close apposition between jSR and mitochondria creates high Ca2+ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca2+ transfer from SR to mitochondria plays a critical role. The SR-mitochondria contacts are established through protein tethers, with mitofusin 2 the most studied SR-mitochondrial "bridge", albeit controversial. Mitochondrial Ca2+ uptake is further optimized with the mitochondrial Ca2+ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na+/Ca2+ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca2+ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca2+ concentrations oscillate in synchronicity with cytosolic Ca2+ transients during heartbeats. Proper Ca2+ transfer controls not only the process of mitochondrial bioenergetics, but also of mitochondria-mediated cell death, autophagy/mitophagy, mitochondrial fusion/fission dynamics, reactive oxygen species generation, and redox signaling, among others. Our review focuses specifically on Ca2+ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca2+ signaling, research gaps, and future trends.
-
5.
Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine.
Grigorian Shamagian, L, Madonna, R, Taylor, D, Climent, AM, Prosper, F, Bras-Rosario, L, Bayes-Genis, A, Ferdinandy, P, Fernández-Avilés, F, Izpisua Belmonte, JC, et al
Circulation research. 2019;(6):938-951
-
-
Free full text
-
Abstract
The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .
-
6.
Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells: Current Strategies and Limitations.
Jiang, Y, Park, P, Hong, SM, Ban, K
Molecules and cells. 2018;(7):613-621
Abstract
The capacity of differentiation of human pluripotent stem cells (hPSCs), which include both embryonic stem cells and induced pluripotent stem cells, into cardiomyocytes (CMs) in vitro provides an unlimited resource for human CMs for a wide range of applications such as cell based cardiac repair, cardiac drug toxicology screening, and human cardiac disease modeling. However, their applicability is significantly limited by immature phenotypes. It has been well known that currently available CMs derived from hPSCs (hPSC-CMs) represent immature embryonic or fetal stage CMs and are functionally and structurally different from mature human CMs. To overcome this critical issue, several new approaches aiming to generate more mature hPSC-CMs have been developed. This review describes recent approaches to generate more mature hPSC-CMs including their scientific principles, advantages, and limitations.
-
7.
Healthy hearts at hectic pace: From daily life stress to abnormal cardiomyocyte function and arrhythmias.
Barbiero, S, Aimo, A, Castiglione, V, Giannoni, A, Vergaro, G, Passino, C, Emdin, M
European journal of preventive cardiology. 2018;(13):1419-1430
Abstract
The hectic pace of contemporary life is a major source of acute and chronic stress, which may have a deleterious impact on body health . In the field of cardiovascular disease, acute emotional stress has been associated with coronary spasm and Takotsubo cardiomyopathy, whereas the manifestations of chronic stress have been overlooked, and most underlying pathophysiology remains to be elucidated. Chronic stress affects the neuronal circuitry composed of cortico-limbic structures and the nuclei regulating autonomic function, eliciting a sympatho-vagal imbalance, characterised by adrenergic activation and vagal withdrawal. Sympathetic terminals are connected to cardiomyocytes in a quasi-synaptic way, producing the so called 'neuro-cardiac junction'. During chronic stress, norepinephrine release is increased, leading to overstimulation of cardiomyocytes via β1-adrenergic receptors, influencing mainly calcium dynamics, and β2-adrenergic receptors, which control housekeeping functions. The circadian rhythm of cardiomyocytes is then impaired, with elongation of the catabolic ('light' phase) over the anabolic ('nocturnal') phase. This leads to a depletion of cell energy storage, and a decreased turnover of cell constituents. Even cell interactions are affected, as coupling between cardiomyocytes decreases while coupling between cardiomyocytes and fibroblasts increases. The ultimate results are changes in the shape and velocity of action potential, fibroblast activation and deposition of extracellular matrix. These alterations may predispose to arrhythmias and may favour the development of a stress-related cardiomyopathy. A better comprehension of this cascade of events may allow us to identify screening protocols and treatment strategies (meditation, yoga, physical activity, psychological assistance, β-blockers) to prevent or relieve ongoing cardiac damage.
-
8.
Dysfunctional Nav1.5 channels due to SCN5A mutations.
Han, D, Tan, H, Sun, C, Li, G
Experimental biology and medicine (Maywood, N.J.). 2018;(10):852-863
-
-
Free full text
-
Abstract
The voltage-gated sodium channel 1.5 (Nav1.5), encoded by the SCN5A gene, is responsible for the rising phase of the action potential of cardiomyocytes. The sodium current mediated by Nav1.5 consists of peak and late components (INa-P and INa-L). Mutant Nav1.5 causes alterations in the peak and late sodium current and is associated with an increasingly wide range of congenital arrhythmias. More than 400 mutations have been identified in the SCN5A gene. Although the mechanisms of SCN5A mutations leading to a variety of arrhythmias can be classified according to the alteration of INa-P and INa-L as gain-of-function, loss-of-function and both, few researchers have summarized the mechanisms in this way before. In this review article, we aim to review the mechanisms underlying dysfunctional Nav1.5 due to SCN5A mutations and to provide some new insights into further approaches in the treatment of arrhythmias. Impact statement The field of ion channelopathy caused by dysfunctional Nav1.5 due to SCN5A mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of various arrhythmias develops. In this review, we focus on the dysfunctional Nav1.5 related to arrhythmias and the underlying mechanisms. We update SCN5A mutations in a precise way since 2013 and presents novel classifications of SCN5A mutations responsible for the dysfunction of the peak (INa-P) and late (INa-L) sodium channels based on their phenotypes, including loss-, gain-, and coexistence of gain- and loss-of function mutations in INa-P, INa-L, respectively. We hope this review will provide a new comprehensive way to better understand the electrophysiological mechanisms underlying arrhythmias from cell to bedside, promoting the management of various arrhythmias in practice.
-
9.
Role of microRNA in metabolic shift during heart failure.
Pinti, MV, Hathaway, QA, Hollander, JM
American journal of physiology. Heart and circulatory physiology. 2017;(1):H33-H45
Abstract
Heart failure (HF) is an end point resulting from a number of disease states. The prognosis for HF patients is poor with survival rates precipitously low. Energy metabolism is centrally linked to the development of HF, and it involves the proteomic remodeling of numerous pathways, many of which are targeted to the mitochondrion. microRNAs (miRNA) are noncoding RNAs that influence posttranscriptional gene regulation. miRNA have garnered considerable attention for their ability to orchestrate changes to the transcriptome, and ultimately the proteome, during HF. Recently, interest in the role played by miRNA in the regulation of energy metabolism at the mitochondrion has emerged. Cardiac proteome remodeling during HF includes axes impacting hypertrophy, oxidative stress, calcium homeostasis, and metabolic fuel transition. Although it is established that the pathological environment of hypoxia and hemodynamic stress significantly contribute to the HF phenotype, it remains unclear as to the mechanistic underpinnings driving proteome remodeling. The aim of this review is to present evidence highlighting the role played by miRNA in these processes as a means for linking pathological stimuli with proteomic alteration. The differential expression of proteins of substrate transport, glycolysis, β-oxidation, ketone metabolism, the citric acid cycle (CAC), and the electron transport chain (ETC) are paralleled by the differential expression of miRNA species that modulate these processes. Identification of miRNAs that translocate to cardiomyocyte mitochondria (miR-181c, miR-378) influencing the expression of the mitochondrial genome-encoded transcripts as well as suggested import modulators are discussed. Current insights, applications, and challenges of miRNA-based therapeutics are also described.
-
10.
A comprehensive review of the bioenergetics of fatty acid and glucose metabolism in the healthy and failing heart in nondiabetic condition.
Gupta, A, Houston, B
Heart failure reviews. 2017;(6):825-842
Abstract
The function of the heart is defined by its ability to deliver adequate cardiac output to meet the requirements of the body both at rest and with exertion. To fill this role, the heart demonstrates an impressive capacity to tightly regulate energy generation and consumption. Energy production and transfer within cardiac myocytes primarily relies on the process of oxidative phosphorylation. In the failing heart, there is an imbalance between the work of the cardiac system and the energy required to generate this work. This presence of this mismatch has given rise to the concept known as the energy starvation theory. This concept encapsulates observations such as perturbed substrate consumption, insufficient energy transfer and ingestion, reduced substrate and oxygen availability, and diminished energy production in the failing heart. Diminished available cellular energy may further result from a reduction in the biosynthesis of mitochondria and their protein synthesis and from global cellular architectural disarray. In essence, the energy starvation theory posits that cardiac pump function declines due to a reduction in oxygen and substrate availability, and thus leads to a total body starvation of systemic energy. This novel cognitive framework has led to encouraging new directions in a "metabolic therapeutic approach" for the failing heart.