Special Issue "Mitochondrial Dynamics: Fusion and Fission"

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

Deadline for manuscript submissions: 28 February 2020.

Special Issue Editor

Prof. P. Hemachandra Reddy
E-Mail Website
Guest Editor
Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430-6540, USA
Interests: aging; mitochondrial dynamics; oxidative stress; mitophagy; neurodegeneration
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The purpose of this Special Issue on ‘Mitochondrial Dynamics: Fusion and Fission’ is to discuss recent developments in mitochondrial dynamics in aging, cancer, cardiovascular, diabetes/obesity, age-related neurodegenerative diseases, and inherited mitochondrial diseases. Mitochondrial dynamics is a delicate balance between division and fusion. In healthy cells, fission and fusion events balance equally, which maintains mitochondrial function. Mitochondria are synthesized in the cell body and travel along axons and dendrites to supply energy to nerve terminals for normal neural communication. In this process, mitochondria alter their shape and size, which facilitates their movement from the cell body to axons, dendrites, and synapses, and back to the cell body. Mitochondria fission is controlled by evolutionary conserved, dynamin-related large GTPases. Fission is regulated by Drp1 and by Fis1, the latter of which is localized in the outer membrane of the mitochondria. When a mitochondrion signals to divide, Drp1 translocates to the outer membrane of the mitochondria, where it initiates the process of fragmentation. By contrast, mitochondria fusion is controlled by 3 GTPase proteins: Mfn1 and Mfn2, which are located in the mitochondrial outer membrane, and Opa1, which is located in the mitochondrial inner membrane. The C-terminal portion of Mfn1 mediates oligomerization between Mfn molecules of adjacent mitochondria, facilitating mt fusion. Recent studies have found increased mitochondrial fission and reduced fusion, suggesting that impaired mitochondrial dynamics is present in aging and age-related neurodegenerative disease. The articles from this Special Issue will provide new information about mitochondrial dynamics, mitochondrial dysfunction, and mitophagy in aging and other human diseases.

Prof. P. Hemachandra Reddy
Guest Editor

Manuscript Submission Information

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Keywords

  • aging
  • mitochondrial dynamics
  • oxidative stress
  • mitophagy
  • neurodegeneration

Published Papers (9 papers)

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Research

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Open AccessArticle
Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells
Cells 2020, 9(2), 301; https://doi.org/10.3390/cells9020301 - 27 Jan 2020
Abstract
Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1, or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal [...] Read more.
Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1, or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene result in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, as well as ATP production and oxygen consumption. It improved mitochondrial morphology in the patient’s fibroblasts, although causing a mild increase in ROS production at the same time. A human foreskin fibroblast cell line overexpressing the p.G362S mutation showed aberrant mitochondrial morphology, which normalized in the presence of bezafibrate. Further studies would be needed to show the consistency of the response to bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that bezafibrate could be offered as a treatment option for patients with certain DNM1L mutations. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessArticle
Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth
Cells 2020, 9(1), 121; https://doi.org/10.3390/cells9010121 - 04 Jan 2020
Abstract
Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to [...] Read more.
Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessArticle
Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death
Cells 2020, 9(1), 116; https://doi.org/10.3390/cells9010116 - 03 Jan 2020
Abstract
It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, [...] Read more.
It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessArticle
The FtsZ Homolog, FszB, Inhibits Mitochondrial Dynamics in Dictyostelium discoideum
Cells 2020, 9(1), 64; https://doi.org/10.3390/cells9010064 - 25 Dec 2019
Abstract
Dictyostelium discoideum is a well-established mitochondrial model system for both disease and dynamics, yet we still do not understand the actual mechanism of mitochondrial dynamics in this system. The FtsZ proteins are known to mediate membrane remodeling events such as cytokinesis in bacteria [...] Read more.
Dictyostelium discoideum is a well-established mitochondrial model system for both disease and dynamics, yet we still do not understand the actual mechanism of mitochondrial dynamics in this system. The FtsZ proteins are known to mediate membrane remodeling events such as cytokinesis in bacteria and fission of chloroplasts; D. discoideum has two FtsZ proteins, FszA and FszB. To determine the role of these proteins in mitochondrial dynamics we overexpressed FszB-GFP and determined its effect on fission, fusion, and motility in the presence of intact and disrupted cytoskeletal filaments. Here we show that overexpression of FszB-GFP decreases mitochondrial dynamics and suggest that actin may play a positive role driving fission in the context of excessive inhibition by overexpressed FszB-GFP. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Review

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Open AccessReview
A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease
Cells 2020, 9(2), 298; https://doi.org/10.3390/cells9020298 - 26 Jan 2020
Abstract
Best known as the powerhouse of the cell, mitochondria have many other important functions such as buffering intracellular calcium and reactive oxygen species levels, initiating apoptosis and supporting cell proliferation and survival. Mitochondria are also dynamic organelles that are constantly undergoing fission and [...] Read more.
Best known as the powerhouse of the cell, mitochondria have many other important functions such as buffering intracellular calcium and reactive oxygen species levels, initiating apoptosis and supporting cell proliferation and survival. Mitochondria are also dynamic organelles that are constantly undergoing fission and fusion to meet specific functional needs. These processes and functions are regulated by intracellular signaling at the mitochondria. A-kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA), other signaling proteins, as well as RNA to the outer mitochondrial membrane. Hence, AKAP1 can be considered a mitochondrial signaling hub. In this review, we discuss what is currently known about AKAP1′s function in health and diseases. We focus on the recent literature on AKAP1′s roles in metabolic homeostasis, cancer and cardiovascular and neurodegenerative diseases. In healthy tissues, AKAP1 has been shown to be important for driving mitochondrial respiration during exercise and for mitochondrial DNA replication and quality control. Several recent in vivo studies using AKAP1 knockout mice have elucidated the role of AKAP1 in supporting cardiovascular, lung and neuronal cell survival in the stressful post-ischemic environment. In addition, we discuss the unique involvement of AKAP1 in cancer tumor growth, metastasis and resistance to chemotherapy. Collectively, the data indicate that AKAP1 promotes cell survival throug regulating mitochondrial form and function. Lastly, we discuss the potential of targeting of AKAP1 for therapy of various disorders. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessReview
Dysregulated Interorganellar Crosstalk of Mitochondria in the Pathogenesis of Parkinson’s Disease
Cells 2020, 9(1), 233; https://doi.org/10.3390/cells9010233 - 17 Jan 2020
Abstract
The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. [...] Read more.
The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. Besides the long-known loss of the organelles’ bioenergetics function resulting in diminished ATP synthesis, more recent studies in the field have increasingly focused on compromised mitochondrial quality control as well as impaired biochemical processes specifically localized to ER–mitochondria interfaces (such as lipid biosynthesis and calcium homeostasis). In this review, we will discuss how dysregulated mitochondrial crosstalk with other organelles contributes to PD pathogenesis. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessReview
Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury
Cells 2020, 9(1), 214; https://doi.org/10.3390/cells9010214 - 15 Jan 2020
Abstract
The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than [...] Read more.
The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes—a phenomenon referred to as ‘lethal myocardial ischemia-reperfusion (IR) injury’. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessReview
Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cells 2020, 9(1), 150; https://doi.org/10.3390/cells9010150 - 08 Jan 2020
Abstract
Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal [...] Read more.
Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer’s disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Open AccessFeature PaperEditor’s ChoiceReview
Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases
Cells 2019, 8(9), 961; https://doi.org/10.3390/cells8090961 - 23 Aug 2019
Cited by 2
Abstract
The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and [...] Read more.
The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases. Full article
(This article belongs to the Special Issue Mitochondrial Dynamics: Fusion and Fission)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Title: Mitochondrial morphosis and myocardial ischemia-reperfusion: deciphering the role of inner versus outer mitochondrial membrane integrity as lynchpins of cardiomyocyte death
Authors: Andrew R. Kulek and Karin Przyklenk
Affiliation: Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA
Article Type: review
Abstract: Mitochondrial morphosis represents a balance between a coupled mitochondrial network (fusion) and fragmented, individual mitochondrion (fission). Ischemia-reperfusion (I/R) injury in heart and other vulnerable organs is associated with a shift to an overall fragmented mitochondrial phenotype and subsequent cell death. It is known that the GTPase proteins OPA1 and DRP1 regulate fission at the inner and outer mitochondrial membranes respectively, yet the significance of OPA1- versus DRP1-mediated events during I/R remains largely unexplored. In this review, we summarize our current understanding of the relative roles of DRP1 and OPA1 as molecular ‘lynchpins’ in lethal myocardial I/R injury.

2. Title: A kinase anchoring protein 1
Author: Stefan Strack
Affiliation: Dept of Pharmacology, University of Iowa Carver College of Medicine, United States
Article Type: review
Abstract: Mitochondria are best known for their role as cellular power plants, but they also serve as signaling hubs, regulating cellular proliferation, differentiation, and survival. A kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA) and other signaling proteins, as well as RNA, to the outer mitochondrial membrane. AKAP1 thereby integrates several second messenger cascades to modulate mitochondrial function and associated physiological and pathophysiological outcomes. Here, we review what is currently known about AKAP1's macromolecular interactions in health and disease states, including obesity. We also discuss dynamin-related protein 1 (Drp1), the enzyme that catalyzes mitochondrial fission, as one of the key substrates of the PKA/AKAP1 signaling complex in neurons. Recent evidence suggests that AKAP1 has critical roles in neuronal development and survival, which are mediated by inhibitory phosphorylation of Drp1 and maintenance of mitochondrial integrity.

3. Author: Xiongwei Zhu
Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
Article type: research article

4. Title: Mitophagy and neurodegeneration
Author: Qian Cai
Affiliation: Cell Biology and Neuroscience, Rutgers University, Piscataway, USA;
The State University of New Jersey, New Brunswick, United States
Article type: review

5. Title: Redox modifications of the mitochondrial fusion and fission machinery
Author: Axel Methner
Affiliation: Johannes Gutenberg University Medical Center Mainz, Mainz, Germany
Article type: review

6. Author: Gilles Gouspillou
Affiliation: Département de Kinanthropologie, Université du Québec à Montréal, Montreal, Quebec, Canada

7. Title: Mitochondrial dynamics in cancer
Author: Kasturi Mitra
Affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
Article type: review

8. Title: Mitochondrial dynamics in the context of Parkinson`s disease
Author: Frank Stephan
Affiliation: Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland
Article type: review

9. Title: Sphingolipids and mitochondrial dynamics
Author: Andréia Leopoldino
Affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
Article type: review

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