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Mitochondrial Dysfunction in Cardiovascular Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 35517

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Special Issue Editor

Dr. Lufang Zhou

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Guest Editor

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: heart failure; cardiac arrhythmias; calcium handling; oxidative stress; mitochondrial dysfunction; optogenetics; computational modeling

Special Issue Information

Dear Colleagues,

Mitochondria lie at the crossroad of cellular metabolic and signaling pathways. Beyond energy production, mitochondria generate key metabolites and biochemical signals crucial for maintaining cell function and health. Studies have shown that functional and structural defects in these vital organelles are implicated in the pathophysiology of cardiovascular disease. Not surprisingly, mitochondrial function has emerged as a promising therapeutic target for cardiovascular disease treatment. However, despite striking outcomes in preclinical studies, the translation of mitochondrial-targeted therapies to the clinic has not been successful to date, suggesting that there is still a lack of an integrative understanding of the mechanisms linking mitochondrial dysfunction and cardiovascular disease.

Cells is planning to publish a Special Issue in Fall 2022 titled “Mitochondrial Dysfunction in Cardiovascular Disease” that will solicit original research articles, short communications, and brief reviews highlighting new and exciting findings in the area of mitochondrial dysfunction in cardiovascular disease. We invite submissions that focus on the mechanisms linking mitochondrial dysfunction and cardiovascular disease and mitochondrial-targeted therapies, including but not limited to mitochondrial-derived signals for cardiac protection; arrhythmias or sudden death; non-coding RNAs; and epigenetic, genetic, and computational approaches for the identification and validation of novel mitochondrial therapeutic targets. Each submitted manuscript will go through a rigorous peer-review process. Submitted manuscripts must not have been published previously nor be under consideration at other journals.

Dr. Lufang Zhou
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cardiovascular disease
mitochondrial dysfunction
mitochondrial targeted therapy
non-coding RNAs
epigenetics
computational model

Published Papers (10 papers)

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Research

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17 pages, 3971 KiB

Open AccessArticle

Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease

by Arpita Deb, Brian D. Tow, You Qing, Madelyn Walker, Emmanuel R. Hodges, James A. Stewart, Jr., Björn C. Knollmann, Yi Zheng, Ying Wang and Bin Liu

Cells 2023, 12(2), 204; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12020204 - 04 Jan 2023

Cited by 1 | Viewed by 2246

Abstract

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca²⁺) release valve to prevent mitochondrial Ca²⁺ (mCa²⁺) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca²⁺ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca²⁺ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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15 pages, 1899 KiB

Open AccessArticle

Does Disruption of Optic Atrophy-1 (OPA1) Contribute to Cell Death in HL-1 Cardiomyocytes Subjected to Lethal Ischemia-Reperfusion Injury?

by Andrew R. Kulek, Vishnu V. R. Undyala, Anthony R. Anzell, Sarita Raghunayakula, Lee Ann MacMillan-Crow, Thomas H. Sanderson and Karin Przyklenk

Cells 2022, 11(19), 3083; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11193083 - 30 Sep 2022

Cited by 1 | Viewed by 1622

Abstract

Disruption of mitochondrial structure/function is well-recognized to be a determinant of cell death in cardiomyocytes subjected to lethal episodes of ischemia-reperfusion (IR). However, the precise mitochondrial event(s) that precipitate lethal IR injury remain incompletely resolved. Using the in vitro HL-1 cardiomyocyte model, our aims were to establish whether: (1) proteolytic processing of optic atrophy protein-1 (OPA1), the inner mitochondrial membrane protein responsible for maintaining cristae junction integrity, plays a causal, mechanistic role in determining cardiomyocyte fate in cells subjected to lethal IR injury; and (2) preservation of OPA1 may contribute to the well-documented cardioprotection achieved with ischemic preconditioning (IPC) and remote ischemic conditioning. We report that HL-1 cells subjected to 2.5 h of simulated ischemia displayed increased activity of OMA1 (the metalloprotease responsible for proteolytic processing of OPA1) during the initial 45 min following reoxygenation. This was accompanied by processing of mitochondrial OPA1 (i.e., cleavage to yield short-OPA1 peptides) and release of short-OPA1 into the cytosol. However, siRNA-mediated knockdown of OPA1 content did not exacerbate lethal IR injury, and did not attenuate the cardioprotection seen with IPC and a remote preconditioning stimulus, achieved by transfer of ‘reperfusate’ medium (TRM-IPC) in this cell culture model. Taken together, our results do not support the concept that maintenance of OPA1 integrity plays a mechanistic role in determining cell fate in the HL-1 cardiomyocyte model of lethal IR injury, or that preservation of OPA1 underlies the cardioprotection seen with ischemic conditioning. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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20 pages, 3171 KiB

Open AccessArticle

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

by Sanna Ryytty, Shalem R. Modi, Nikolay Naumenko, Anastasia Shakirzyanova, Muhammad Obaidur Rahman, Miia Vaara, Anu Suomalainen, Pasi Tavi and Riikka H. Hämäläinen

Cells 2022, 11(16), 2593; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162593 - 19 Aug 2022

Cited by 5 | Viewed by 2304

Abstract

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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21 pages, 13676 KiB

Open AccessEditor’s ChoiceArticle

Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury

by Lihao He, Yuxin Chu, Jing Yang, Jin He, Yutao Hua, Yunxi Chen, Gloria Benavides, Glenn C. Rowe, Lufang Zhou, Scott Ballinger, Victor Darley-Usmar, Martin E. Young, Sumanth D. Prabhu, Palaniappan Sethu, Yingling Zhou, Cheng Zhang and Min Xie

Cells 2022, 11(13), 2111; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132111 - 04 Jul 2022

Cited by 7 | Viewed by 2460

Abstract

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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28 pages, 41826 KiB

Open AccessArticle

Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney

by Xiao Zhang, Namrata Tomar, Sunil M. Kandel, Said H. Audi, Allen W. Cowley, Jr. and Ranjan K. Dash

Cells 2022, 11(1), 131; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010131 - 31 Dec 2021

Cited by 10 | Viewed by 2909

Abstract

Mitochondrial dehydrogenases are differentially stimulated by Ca²⁺. Ca²⁺ has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl₂ concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca²⁺ effects are biphasic: small increases in Ca²⁺ concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca²⁺-dependent O₂ utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca²⁺ showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca²⁺ had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca²⁺ on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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Review

Jump to: Research

27 pages, 1864 KiB

Open AccessReview

Mitochondrial Dysfunction in Cardiac Arrhythmias

by Jielin Deng, Yunqiu Jiang, Zhen Bouman Chen, June-Wha Rhee, Yingfeng Deng and Zhao V. Wang

Cells 2023, 12(5), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12050679 - 21 Feb 2023

Cited by 8 | Viewed by 5286

Abstract

Electrophysiological and structural disruptions in cardiac arrhythmias are closely related to mitochondrial dysfunction. Mitochondria are an organelle generating ATP, thereby satisfying the energy demand of the incessant electrical activity in the heart. In arrhythmias, the homeostatic supply–demand relationship is impaired, which is often accompanied by progressive mitochondrial dysfunction leading to reduced ATP production and elevated reactive oxidative species generation. Furthermore, ion homeostasis, membrane excitability, and cardiac structure can be disrupted through pathological changes in gap junctions and inflammatory signaling, which results in impaired cardiac electrical homeostasis. Herein, we review the electrical and molecular mechanisms of cardiac arrhythmias, with a particular focus on mitochondrial dysfunction in ionic regulation and gap junction action. We provide an update on inherited and acquired mitochondrial dysfunction to explore the pathophysiology of different types of arrhythmias. In addition, we highlight the role of mitochondria in bradyarrhythmia, including sinus node dysfunction and atrioventricular node dysfunction. Finally, we discuss how confounding factors, such as aging, gut microbiome, cardiac reperfusion injury, and electrical stimulation, modulate mitochondrial function and cause tachyarrhythmia. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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37 pages, 2772 KiB

Open AccessReview

Kinetic Mathematical Modeling of Oxidative Phosphorylation in Cardiomyocyte Mitochondria

by Wen-Wei Tseng and An-Chi Wei

Cells 2022, 11(24), 4020; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244020 - 12 Dec 2022

Cited by 3 | Viewed by 2381

Abstract

Oxidative phosphorylation (OXPHOS) is an oxygen-dependent process that consumes catabolized nutrients to produce adenosine triphosphate (ATP) to drive energy-dependent biological processes such as excitation-contraction coupling in cardiomyocytes. In addition to in vivo and in vitro experiments, in silico models are valuable for investigating the underlying mechanisms of OXPHOS and predicting its consequences in both physiological and pathological conditions. Here, we compare several prominent kinetic models of OXPHOS in cardiomyocytes. We examine how their mathematical expressions were derived, how their parameters were obtained, the conditions of their experimental counterparts, and the predictions they generated. We aim to explore the general landscape of energy production mechanisms in cardiomyocytes for future in silico models. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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27 pages, 2131 KiB

Open AccessReview

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy

by Teresa Campbell, Jesse Slone and Taosheng Huang

Cells 2022, 11(18), 2835; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182835 - 11 Sep 2022

Cited by 4 | Viewed by 2935

Abstract

Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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17 pages, 1660 KiB

Open AccessReview

Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease

by Lai-Hua Xie, Nadezhda Fefelova, Sri Harika Pamarthi and Judith K. Gwathmey

Cells 2022, 11(17), 2726; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172726 - 01 Sep 2022

Cited by 44 | Viewed by 7903

Abstract

Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis by promoting the generation of both soluble and lipid ROS via an iron-dependent Fenton reaction and lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with ferroptosis suppressor protein 1 (FSP1) and mitochondrial glutathione peroxidase 4 (mGPX4) pairing with dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems to detoxify lipid peroxidation in the cytoplasmic as well as the mitochondrial membrane, thereby defending against ferroptosis in cells under normal conditions. However, disruption of these defense systems may cause ferroptosis. Emerging evidence has revealed that ferroptosis plays an essential role in the development of diverse cardiovascular diseases (CVDs), such as hemochromatosis-associated cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia/reperfusion (I/R) injury, heart failure (HF), atherosclerosis, and COVID-19–related arrhythmias. Iron chelators, antioxidants, ferroptosis inhibitors, and genetic manipulations may alleviate the aforementioned CVDs by blocking ferroptosis pathways. In conclusion, ferroptosis plays a critical role in the pathogenesis of various CVDs and suppression of cardiac ferroptosis is expected to become a potential therapeutic option. Here, we provide a comprehensive review on the molecular mechanisms involved in ferroptosis and its implications in cardiovascular disease. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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20 pages, 1468 KiB

Open AccessEditor’s ChoiceReview

Genetically Encoded ATP Biosensors for Direct Monitoring of Cellular ATP Dynamics

by Donnell White III and Qinglin Yang

Cells 2022, 11(12), 1920; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121920 - 14 Jun 2022

Cited by 13 | Viewed by 4211

Abstract

Adenosine 5′-triphosphate, or ATP, is the primary molecule for storing and transferring energy in cells. ATP is mainly produced via oxidative phosphorylation in mitochondria, and to a lesser extent, via glycolysis in the cytosol. In general, cytosolic glycolysis is the primary ATP producer in proliferative cells or cells subjected to hypoxia. On the other hand, mitochondria produce over 90% of cellular ATP in differentiated cells under normoxic conditions. Under pathological conditions, ATP demand rises to meet the needs of biosynthesis for cellular repair, signaling transduction for stress responses, and biochemical processes. These changes affect how mitochondria and cytosolic glycolysis function and communicate. Mitochondria undergo remodeling to adapt to the imbalanced demand and supply of ATP. Otherwise, a severe ATP deficit will impair cellular function and eventually cause cell death. It is suggested that ATP from different cellular compartments can dynamically communicate and coordinate to adapt to the needs in each cellular compartment. Thus, a better understanding of ATP dynamics is crucial to revealing the differences in cellular metabolic processes across various cell types and conditions. This requires innovative methodologies to record real-time spatiotemporal ATP changes in subcellular regions of living cells. Over the recent decades, numerous methods have been developed and utilized to accomplish this task. However, this is not an easy feat. This review evaluates innovative genetically encoded biosensors available for visualizing ATP in living cells, their potential use in the setting of human disease, and identifies where we could improve and expand our abilities. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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