Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders.

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When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22094617 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4617

Author(s):

Styliana Kyriakoudi ◽

Anthi Drousiotou ◽

Petros P. Petrou

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Human Disease ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Mitochondrial Morphology ◽

Disease Development ◽

Pathological Conditions ◽

Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

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Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Life ◽

10.3390/life11040332 ◽

2021 ◽

Vol 11 (4) ◽

pp. 332

Author(s):

Valentina Brillo ◽

Leonardo Chieregato ◽

Luigi Leanza ◽

Silvia Muccioli ◽

Roberto Costa

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Eukaryotic Cells ◽

Therapeutic Approaches ◽

Cellular Functions ◽

Lipid Trafficking ◽

Mitochondrial Ros ◽

Intracellular Organelles ◽

Proliferation Regulation ◽

Dynamic Plasticity

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

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TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus Via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics

Cells ◽

10.3390/cells8111376 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1376 ◽

Cited By ~ 2

Author(s):

Kim ◽

Park ◽

Choi ◽

Kong ◽

Kang

Keyword(s):

Status Epilepticus ◽

Granule Cell ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Mitochondrial Dynamics ◽

Neurological Diseases ◽

Mitochondrial Fission ◽

Receptor Potential ◽

Lon Protease ◽

Dentate Granule Cell

Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca2+-permeable non-selective cation channels. TRPC6 is mainly expressed in dentate granule cell (DGC), which is one of the most resistant neuronal populations to various harmful stresses. Although TRPC6 knockdown evokes the massive DGC degeneration induced by status epilepticus (a prolonged seizure activity, SE), the molecular mechanisms underlying the role of TRPC6 in DGC viability in response to SE are still unclear. In the present study, hyperforin (a TRPC6 activator) facilitated mitochondrial fission in DGC concomitant with increases in Lon protease-1 (LONP1, a mitochondrial protease) expression and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation under physiological conditions, which were abrogated by U0126 (an ERK1/2 inhibitor) co-treatment. TRPC6 knockdown showed the opposite effects on LONP1 expression, ERK1/2 activity, and mitochondrial dynamics. In addition, TRPC6 siRNA and U0126 evoked the massive DGC degeneration accompanied by mitochondrial elongation following SE, independent of seizure severity. However, LONP1 siRNA exacerbated SE-induced DGC death without affecting mitochondrial length. These findings indicate that TRPC6-ERK1/2 activation may increase DGC invulnerability to SE by regulating LONP1 expression as well as mitochondrial dynamics. Therefore, TRPC6-ERK1/2-LONP1 signaling pathway will be an interesting and important therapeutic target for neuroprotection from various neurological diseases.

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Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

10.1101/592915 ◽

2019 ◽

Author(s):

Yanjun Kou ◽

Yunlong He ◽

Jiehua Qiu ◽

Shu Yazhou ◽

Fan Yang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Morphological Changes ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Blast Disease ◽

Cereal Crops ◽

Mitochondrial Morphology ◽

Invasive Growth ◽

In Planta ◽

Antioxidant Treatment

SUMMARYMagnaporthe oryzaecauses Blast disease, which is one of the most devastating infections in rice and several important cereal crops.M. oryzaeneeds to coordinate gene regulation, morphological changes, nutrient acquisition, and host evasion, in order to invade and proliferate within the plant tissues. Thus far, the molecular mechanisms underlying the regulation of invasive growthin plantahave remained largely unknown. We identified a precise filamentous-punctate-filamentous cycle in mitochondrial morphology duringMagnaporthe-Rice interaction. Interestingly, loss of either the mitochondrial fusion (MoFzo1) or fission (MoDnm1) machinery, or inhibition of mitochondrial fission using Mdivi-1 caused significant reduction inM. oryzaepathogenicity. Furthermore, exogenous carbon source(s) but not antioxidant treatment delayed such mitochondrial dynamics/transition during invasive growth. Such nutrient-based regulation of organellar dynamics preceded MoAtg24-mediated mitophagy, which was found to be essential for proper biotrophic development and invasive growthin planta. We propose that precise mitochondrial dynamics and mitophagy occur during the transition from biotrophy to necrotrophy, and are required for proper induction and establishment of the blast disease in rice.

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Abstract 568: Deletion of AMP-activated Protein Kinase-alpha Triggers Mitochondrial Fission and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.568 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Qqilong Wang ◽

Zhonglin Xie ◽

Huaiping Zhu ◽

Ye Ding ◽

Ming-Hui Zou

Keyword(s):

Protein Kinase ◽

Endothelial Dysfunction ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Chronic Administration ◽

Mitochondrial Fragmentation ◽

Aortic Endothelium ◽

Amp Activated Protein Kinase

Introduction: AMP-activated protein kinase (AMPK) has been reported to regulate mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which AMPK regulates mitochondrial dynamics remain poorly characterized. We hypothesized that AMPK deficiency regulates mitochondrial fission that will result in endothelial dysfunction. Methods/Results: Deletion of AMPKα2 resulted in defective autophagy, dynamin-related protein (Drp1) accumulation, and aberrant mitochondrial fragmentation in the aortic endothelium of mice. Furthermore, autophagy inhibition by chloroquine treatment or Atg7 small interfering RNA (siRNA) transfection upregulated Drp1 expression and triggered Drp1-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of Atg7 or chronic administration of rapamycin, the mammalian target of rapamycin kinase inhibitor, promoted Drp1 degradation and attenuated mitochondrial fission in AMPKα2 -/- mice, suggesting that defective autophagy contributes to enhanced Drp1 expression and mitochondrial fragmentation. Interesting, the genetic (Drp1 siRNA) or pharmacological (mdivi-1) inhibition of Drp1 ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas from AMPKα2 -/- mice. This suggests that aberrant Drp1 is responsible for enhanced mitochondrial fission and endothelial dysfunction in AMPKα knockout mice. Conclusions: Our results show that AMPKα deletion promoted mitochondrial fission in vascular endothelial cells by inhibiting the autophagy-dependent degradation of Drp1.

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Mitochondrial dynamics: overview of molecular mechanisms

Essays in Biochemistry ◽

10.1042/ebc20170104 ◽

2018 ◽

Vol 62 (3) ◽

pp. 341-360 ◽

Cited By ~ 197

Author(s):

Lisa Tilokani ◽

Shun Nagashima ◽

Vincent Paupe ◽

Julien Prudent

Keyword(s):

Membrane Fusion ◽

Mitochondrial Membrane ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Membrane Lipid ◽

Inner Mitochondrial Membrane ◽

Step Process ◽

Shape Distribution

Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

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Huntingtin–HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease

The Journal of Cell Biology ◽

10.1083/jcb.200509091 ◽

2006 ◽

Vol 172 (4) ◽

pp. 605-618 ◽

Cited By ~ 128

Author(s):

Arun Pal ◽

Fedor Severin ◽

Barbara Lommer ◽

Anna Shevchenko ◽

Marino Zerial

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Actin Filaments ◽

Molecular Mechanisms ◽

Early Endosome ◽

Drastic Reduction ◽

Pathological Conditions ◽

Early Endosomes ◽

Guanosine Triphosphatase ◽

Endocytic Activity

The molecular mechanisms underlying the targeting of Huntingtin (Htt) to endosomes and its multifaceted role in endocytosis are poorly understood. In this study, we have identified Htt-associated protein 40 (HAP40) as a novel effector of the small guanosine triphosphatase Rab5, a key regulator of endocytosis. HAP40 mediates the recruitment of Htt by Rab5 onto early endosomes. HAP40 overexpression caused a drastic reduction of early endosomal motility through their displacement from microtubules and preferential association with actin filaments. Remarkably, endogenous HAP40 was up-regulated in fibroblasts and brain tissue from human patients affected by Huntington's disease (HD) as well as in STHdhQ111 striatal cells established from a HD mouse model. These cells consistently displayed altered endosome motility and endocytic activity, which was restored by the ablation of HAP40. In revealing an unexpected link between Rab5, HAP40, and Htt, we uncovered a new mechanism regulating cytoskeleton-dependent endosome dynamics and its dysfunction under pathological conditions.

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Mitochondrial Dynamics and VMP1-Related Selective Mitophagy in Experimental Acute Pancreatitis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.640094 ◽

2021 ◽

Vol 9 ◽

Author(s):

Virginia Vanasco ◽

Alejandro Ropolo ◽

Daniel Grasso ◽

Diego S. Ojeda ◽

María Noé García ◽

...

Keyword(s):

Acute Pancreatitis ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Cell Model ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Pancreatic Acinar Cells ◽

Atp Production ◽

Selective Autophagy ◽

Mild Disease

Mitophagy and zymophagy are selective autophagy pathways early induced in acute pancreatitis that may explain the mild, auto limited, and more frequent clinical presentation of this disease. Adequate mitochondrial bioenergetics is necessary for cellular restoration mechanisms that are triggered during the mild disease. However, mitochondria and zymogen contents are direct targets of damage in acute pancreatitis. Cellular survival depends on the recovering possibility of mitochondrial function and efficient clearance of damaged mitochondria. This work aimed to analyze mitochondrial dynamics and function during selective autophagy in pancreatic acinar cells during mild experimental pancreatitis in rats. Also, using a cell model under the hyperstimulation of the G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanisms involved in these processes in the context of zymophagy. We found that during acute pancreatitis, mitochondrial O2consumption and ATP production significantly decreased early after induction of acute pancreatitis, with a consequent decrease in the ATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrial dynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1) differential expression and ultrastructural features of mitochondrial fission, mitochondrial elongation, and mitophagy during the acute phase of experimental mild pancreatitis in rats. Mitophagy was also evaluated by confocal assay after transfection with the pMITO-RFP-GFP plasmid that specifically labels autophagic degradation of mitochondria and the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, we report for the first time that vacuole membrane protein-1 (VMP1) is involved and required in the mitophagy process during acute pancreatitis, observable not only by repositioning around specific mitochondrial populations, but also by detection of mitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies as well. Also, VMP1 downregulation avoided mitochondrial degradation confirming that VMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, we identified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis. The understanding of the molecular mechanisms involved to restore mitochondrial function, such as mitochondrial dynamics and mitophagy, could be relevant in the development of novel therapeutic strategies in acute pancreatitis.

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Identification of Elongation Factor-2 as a Novel Regulator of Mitochondrial Fission

10.21203/rs.3.rs-778562/v1 ◽

2021 ◽

Author(s):

Jinhwan Kim ◽

Yan Cheng ◽

Yanfeng Li ◽

Yi Zhang ◽

Ji Cheng ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Critical Role ◽

Elongation Factor ◽

Binding Motif ◽

Gtpase Activity ◽

Elongation Factor 2 ◽

Gtp Binding ◽

And Function

Abstract Mitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G-protein superfamily member encoded by EEF2 gene in human, has long been appreciated as a promoter of the GTP-dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, co-localized at the mitochondria, as evidenced by microscopic observation, co-immunoprecipitation, and GST pulldown assay. Deletion of the GTP binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild-type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria-related diseases.

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Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis

Life ◽

10.3390/life11020165 ◽

2021 ◽

Vol 11 (2) ◽

pp. 165

Author(s):

Alexander M. Markin ◽

Viktoria A. Khotina ◽

Xenia G. Zabudskaya ◽

Anastasia I. Bogatyreva ◽

Antonina V. Starodubova ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Energy Production ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Living Cells ◽

Therapeutic Approaches ◽

Energy Needs ◽

Wide Range ◽

Human Disorders ◽

Mitochondrial Turnover

Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death—features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.

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