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23 pages, 3755 KiB

Open AccessArticle

Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function

by Jian Xiong, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du and Michael X. Zhu

Cells 2023, 12(1), 80; https://doi.org/10.3390/cells12010080 - 24 Dec 2022

Cited by 5 | Viewed by 3156

Abstract

Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH [...] Read more.

Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino acids from the culture medium enhanced lysosomal degradation similarly as total amino acid starvation. The presence of glutamine in regular culture media increased lysosomal pH by >0.5 pH unit and the removal of glutamine caused lysosomal acidification. GLS1/2 knockdown, GLS1 antagonist, or ammonium scavengers reduced lysosomal pH in the presence of glutamine. The addition of glutamine or NH₄Cl prevented the increase in lysosomal degradation and curtailed the extension of mTORC1 function during the early time period of amino acid starvation. Our findings suggest that glutamine tunes lysosomal pH by producing ammonium, which regulates lysosomal degradation to meet the demands of cellular activities. During the early stage of amino acid starvation, the glutamine-dependent mechanism allows more efficient use of internal reserves and endocytosed proteins to extend mTORC1 activation such that the normal anabolism is not easily interrupted by a brief disruption of the amino acid supply. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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19 pages, 29063 KiB

Open AccessEditor’s ChoiceArticle

CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology

by Kariana E. Rios, Ming Zhou, Nathaniel M. Lott, Chelsi R. Beauregard, Dennis P. McDaniel, Thomas P. Conrads and Brian C. Schaefer

Cells 2022, 11(7), 1175; https://doi.org/10.3390/cells11071175 - 31 Mar 2022

Cited by 1 | Viewed by 4083

Abstract

CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8⁺ T cells. Here, we employ a combination of SIM, [...] Read more.

CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8⁺ T cells. Here, we employ a combination of SIM, TEM, and confocal microscopy, along with proteinase K protection assays and proteomics approaches, to identify interacting partners of CARD19 in macrophages. Our data show that CARD19 is specifically localized to the outer mitochondrial membrane. Through deletion of functional domains, we demonstrate that both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD is not. Importantly, mass spectrometry analysis of 3×Myc-CARD19 immunoprecipitates reveals that CARD19 interacts with the components of the mitochondrial intermembrane bridge (MIB), consisting of mitochondrial contact site and cristae organizing system (MICOS) components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These CARD19 interactions are in part dependent on a properly folded CARD. Consistent with previously reported phenotypes upon siRNA silencing of MICOS subunits, absence of CARD19 correlates with irregular cristae morphology. Based on these data, we propose that CARD19 is a previously unknown interacting partner of the MIB and the MIC19–MIC25–MIC60 MICOS subcomplex that regulates cristae morphology. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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29 pages, 4083 KiB

Open AccessArticle

C53 Interacting with UFM1-Protein Ligase 1 Regulates Microtubule Nucleation in Response to ER Stress

by Anastasiya Klebanovych, Stanislav Vinopal, Eduarda Dráberová, Vladimíra Sládková, Tetyana Sulimenko, Vadym Sulimenko, Věra Vosecká, Libor Macůrek, Agustin Legido and Pavel Dráber

Cells 2022, 11(3), 555; https://doi.org/10.3390/cells11030555 - 5 Feb 2022

Cited by 7 | Viewed by 3393

Abstract

ER distribution depends on microtubules, and ER homeostasis disturbance activates the unfolded protein response resulting in ER remodeling. CDK5RAP3 (C53) implicated in various signaling pathways interacts with UFM1-protein ligase 1 (UFL1), which mediates the ufmylation of proteins in response to ER stress. Here [...] Read more.

ER distribution depends on microtubules, and ER homeostasis disturbance activates the unfolded protein response resulting in ER remodeling. CDK5RAP3 (C53) implicated in various signaling pathways interacts with UFM1-protein ligase 1 (UFL1), which mediates the ufmylation of proteins in response to ER stress. Here we find that UFL1 and C53 associate with γ-tubulin ring complex proteins. Knockout of UFL1 or C53 in human osteosarcoma cells induces ER stress and boosts centrosomal microtubule nucleation accompanied by γ-tubulin accumulation, microtubule formation, and ER expansion. C53, which is stabilized by UFL1, associates with the centrosome and rescues microtubule nucleation in cells lacking UFL1. Pharmacological induction of ER stress by tunicamycin also leads to increased microtubule nucleation and ER expansion. Furthermore, tunicamycin suppresses the association of C53 with the centrosome. These findings point to a novel mechanism for the relief of ER stress by stimulation of centrosomal microtubule nucleation. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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19 pages, 2198 KiB

Open AccessEditor’s ChoiceArticle

Mitochondria-Endoplasmic Reticulum Interplay Regulates Exo-Cytosis in Human Neuroblastoma Cells

by Giacomo Dentoni, Luana Naia and Maria Ankarcrona

Cells 2022, 11(3), 514; https://doi.org/10.3390/cells11030514 - 2 Feb 2022

Cited by 6 | Viewed by 3394

Abstract

Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the [...] Read more.

Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the role of these contacts in exocytosis and find potential mechanisms linking these structures to vesicle release in human neuroblastoma SH-SY5Y cells. We show that increased mitochondria to ER juxtaposition through Mitofusin 2 (Mfn2) knock-down resulted in a substantial upregulation of the number of MERCS, confirming the role of Mfn2 as a negative regulator of these structures. Furthermore, we report that both vesicle numbers and vesicle protein levels were decreased, while a considerable upregulation in exocytotic events upon cellular depolarization was detected. Interestingly, in Mfn2 knock-down cells, the inhibition of the inositol 1,4,5-trisphosphate receptor (IP3R) and the mitochondrial calcium (Ca²⁺) uniporter (MCU) restored vesicle protein content and attenuated exocytosis. We thus suggest that MERCS could be targeted to prevent increased exocytosis in conditions in which ER to mitochondria proximity is upregulated. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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12 pages, 1691 KiB

Open AccessEditor’s ChoiceArticle

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

by Silvia Graziani, Luca Scorrano and Giovanna Pontarin

Cells 2022, 11(2), 210; https://doi.org/10.3390/cells11020210 - 8 Jan 2022

Cited by 16 | Viewed by 3890

Abstract

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how [...] Read more.

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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22 pages, 2463 KiB

Open AccessArticle

Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts

by Ajibola B. Bakare, Raj R. Rao and Shilpa Iyer

Cells 2021, 10(9), 2255; https://doi.org/10.3390/cells10092255 - 31 Aug 2021

Cited by 7 | Viewed by 4180

Abstract

Mitochondrial disorders represent a large group of severe genetic disorders mainly impacting organ systems with high energy requirements. Leigh syndrome (LS) is a classic example of a mitochondrial disorder resulting from pathogenic mutations that disrupt oxidative phosphorylation capacities. Currently, evidence-based therapy directed towards [...] Read more.

Mitochondrial disorders represent a large group of severe genetic disorders mainly impacting organ systems with high energy requirements. Leigh syndrome (LS) is a classic example of a mitochondrial disorder resulting from pathogenic mutations that disrupt oxidative phosphorylation capacities. Currently, evidence-based therapy directed towards treating LS is sparse. Recently, the cell-permeant substrates responsible for regulating the electron transport chain have gained attention as therapeutic agents for mitochondrial diseases. We explored the therapeutic effects of introducing tricarboxylic acid cycle (TCA) intermediate substrate, succinate, as a cell-permeable prodrug NV118, to alleviate some of the mitochondrial dysfunction in LS. The results suggest that a 24-hour treatment with prodrug NV118 elicited an upregulation of glycolysis and mitochondrial membrane potential while inhibiting intracellular reactive oxygen species in LS cells. The results from this study suggest an important role for TCA intermediates for treating mitochondrial dysfunction in LS. We show, here, that NV118 could serve as a therapeutic agent for LS resulting from mutations in mtDNA in complex I and complex V dysfunctions. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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19 pages, 5507 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

by Troy A. Kervin and Michael Overduin

Cells 2021, 10(5), 1205; https://doi.org/10.3390/cells10051205 - 14 May 2021

Cited by 9 | Viewed by 4970

Abstract

The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which [...] Read more.

The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which demark organelles to initiate localized trafficking and signaling events. The only superfamily which specifically detects all seven PIPs are the Phox homology (PX) domains. Here, we reveal that throughout evolution, these readers are universally regulated by the phosphorylation of their PIP binding surfaces based on our analysis of existing and modelled protein structures and phosphoproteomic databases. These PIP-stops control the selective targeting of proteins to organelles and are shown to be key determinants of high-fidelity PIP recognition. The protein kinases responsible include prominent cancer targets, underscoring the critical role of regulated membrane readership. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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14 pages, 7443 KiB

Open AccessArticle

Chemical Inhibitors of Dynamin Exert Differential Effects in VEGF Signaling

by Dimitris Basagiannis, Sofia Zografou, Evangeli Goula, Despoina Gkeka, Evangelos Kolettas and Savvas Christoforidis

Cells 2021, 10(5), 997; https://doi.org/10.3390/cells10050997 - 23 Apr 2021

Cited by 11 | Viewed by 3651

Abstract

VEGFR2 is the main receptor and mediator of the vasculogenic and angiogenic activity of VEGF. Activated VEGFR2 internalizes through clathrin-mediated endocytosis and macropinocytosis. As dynamin is a key regulator of the clathrin pathway, chemical inhibitors of dynamin are commonly used to assess the [...] Read more.

VEGFR2 is the main receptor and mediator of the vasculogenic and angiogenic activity of VEGF. Activated VEGFR2 internalizes through clathrin-mediated endocytosis and macropinocytosis. As dynamin is a key regulator of the clathrin pathway, chemical inhibitors of dynamin are commonly used to assess the role of the clathrin route in receptor signaling. However, drugs may also exert off-target effects. Here, we compare the effects of three dynamin inhibitors, dynasore, dyngo 4a and dynole, on VEGFR2 internalization and signaling. Although these drugs consistently inhibit clathrin-mediated endocytosis of both transferrin (a typical cargo of this route) and VEGFR2, surprisingly, they exert contradictory effects in receptor signaling. Thus, while dynasore has no effect on phosphorylation of VEGFR2, the other two drugs are strong inhibitors. Furthermore, although dyngo does not interfere with phosphorylation of Akt, dynasore and dynole have a strong inhibitory effect. These inconsistent effects suggest that the above dynamin blockers, besides inhibiting dynamin-dependent endocytosis of VEGFR2, exert additional inhibitory effects on signaling that are independent of endocytosis; i.e., they are due to off-target effects. Using a recently developed protocol, we comparatively validate the specificity of two endocytic inhibitors, dynasore and EIPA. Our findings highlight the importance of assessing whether the effect of an endocytic drug on signaling is specifically due to its interference with endocytosis or due to off-targets. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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Review

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9 pages, 795 KiB

Open AccessEditor’s ChoiceReview

Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

by Annunziata Cascone, Maciej Lalowski, Dan Lindholm and Ove Eriksson

Cells 2022, 11(10), 1703; https://doi.org/10.3390/cells11101703 - 20 May 2022

Cited by 6 | Viewed by 3085

Abstract

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to [...] Read more.

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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17 pages, 9243 KiB

Open AccessReview

Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways

by Ron Benyair, Avital Eisenberg-Lerner and Yifat Merbl

Cells 2022, 11(5), 780; https://doi.org/10.3390/cells11050780 - 23 Feb 2022

Cited by 10 | Viewed by 4311

Abstract

The Golgi apparatus is a central hub for cellular protein trafficking and signaling. Golgi structure and function is tightly coupled and undergoes dynamic changes in health and disease. A crucial requirement for maintaining Golgi homeostasis is the ability of the Golgi to target [...] Read more.

The Golgi apparatus is a central hub for cellular protein trafficking and signaling. Golgi structure and function is tightly coupled and undergoes dynamic changes in health and disease. A crucial requirement for maintaining Golgi homeostasis is the ability of the Golgi to target aberrant, misfolded, or otherwise unwanted proteins to degradation. Recent studies have revealed that the Golgi apparatus may degrade such proteins through autophagy, retrograde trafficking to the ER for ER-associated degradation (ERAD), and locally, through Golgi apparatus-related degradation (GARD). Here, we review recent discoveries in these mechanisms, highlighting the role of the Golgi in maintaining cellular homeostasis. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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17 pages, 1704 KiB

Open AccessReview

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

by Stan W. van Wijk, Wei Su, Leonoor F. J. M. Wijdeveld, Kennedy S. Ramos and Bianca J. J. M. Brundel

Cells 2022, 11(3), 416; https://doi.org/10.3390/cells11030416 - 25 Jan 2022

Cited by 7 | Viewed by 5263

Abstract

The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1–2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In [...] Read more.

The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1–2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In these families, genome and exome sequencing techniques identified variants in the non-coding genome (i.e., variant regulatory elements), genes encoding ion channels, as well as genes encoding cytoskeletal (-associated) proteins. Cytoskeletal protein variants include variants in desmin, lamin A/C, titin, myosin heavy and light chain, junctophilin, nucleoporin, nesprin, and filamin C. These cytoskeletal protein variants have a strong association with the development of cardiomyopathy. Interestingly, AF onset is often represented as the initial manifestation of cardiac disease, sometimes even preceding cardiomyopathy by several years. Although emerging research findings reveal cytoskeletal protein variants to disrupt the cardiomyocyte structure and trigger DNA damage, exploration of the pathophysiological mechanisms of genetic AF is still in its infancy. In this review, we provide an overview of cytoskeletal (-associated) gene variants that relate to genetic AF and highlight potential pathophysiological pathways that drive this arrhythmia. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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12 pages, 1571 KiB

Open AccessReview

Emerging Lysosomal Functions for Photoreceptor Cell Homeostasis and Survival

by Manuela Santo and Ivan Conte

Cells 2022, 11(1), 60; https://doi.org/10.3390/cells11010060 - 26 Dec 2021

Cited by 6 | Viewed by 3757

Abstract

Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the [...] Read more.

Lysosomes are membrane-bound cell organelles that respond to nutrient changes and are implicated in cell homeostasis and clearance mechanisms, allowing effective adaptation to specific cellular needs. The relevance of the lysosome has been elucidated in a number of different contexts. Of these, the retina represents an interesting scenario to appreciate the various functions of this organelle in both physiological and pathological conditions. Growing evidence suggests a role for lysosome-related mechanisms in retinal degeneration. Abnormal lysosomal activation or inhibition has dramatic consequences on photoreceptor cell homeostasis and impacts extensive cellular function, which in turn affects vision. Based on these findings, a series of therapeutic methods targeting lysosomal processes could offer treatment for blindness conditions. Here, we review the recent findings on membrane trafficking, subcellular organization, mechanisms by which lysosome/autophagy pathway impairment affects photoreceptor cell homeostasis and the recent advances on developing efficient lysosomal-based therapies for retinal disorders. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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23 pages, 1309 KiB

Open AccessReview

Protein Aggregation in the ER: Calm behind the Storm

by Haisen Li and Shengyi Sun

Cells 2021, 10(12), 3337; https://doi.org/10.3390/cells10123337 - 28 Nov 2021

Cited by 23 | Viewed by 4836

Abstract

As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding [...] Read more.

As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly, and/or defects or limited capacities of the protein quality control systems, nascent proteins may become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to the so-called “ER storage diseases”. In this review, we first summarize our current understanding of the protein folding and quality control networks in the ER, including chaperones, unfolded protein response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy). We then survey recent research progress on a few ER storage diseases, with a focus on the role of ER quality control in the disease etiology, followed by a discussion on outstanding questions and emerging concepts in the field. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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17 pages, 920 KiB

Open AccessFeature PaperReview

Acetylation in Mitochondria Dynamics and Neurodegeneration

by Jaylyn Waddell, Aditi Banerjee and Tibor Kristian

Cells 2021, 10(11), 3031; https://doi.org/10.3390/cells10113031 - 5 Nov 2021

Cited by 8 | Viewed by 3898

Abstract

Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is [...] Read more.

Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is fine-tuned by a specific group of proteins and their complex post-translational modifications. In this review, we discuss the mitochondrial dynamics regulatory enzymes, their adaptor proteins, and the effect of acetylation on the activity of fusion and fission machinery as a ubiquitous response to metabolic stresses. Further, we discuss the role of intracellular cytoskeleton structures and their post-translational modifications in the modulation of mitochondrial fusion and fission. Finally, we review the role of mitochondrial dynamics dysregulation in the pathophysiology of acute brain injury and the treatment strategies based on modulation of NAD⁺-dependent deacetylation. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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15 pages, 1138 KiB

Open AccessEditor’s ChoiceReview

Circadian Organelles: Rhythms at All Scales

by Rona Aviram, Yaarit Adamovich and Gad Asher

Cells 2021, 10(9), 2447; https://doi.org/10.3390/cells10092447 - 16 Sep 2021

Cited by 7 | Viewed by 4042

Abstract

Circadian clocks have evolved in most light-sensitive organisms, from unicellular organisms to mammals. Consequently, a myriad of biological functions exhibits circadian rhythmicity, from behavior to physiology, through tissue and cellular functions to subcellular processes. Circadian rhythms in intracellular organelles are an emerging and [...] Read more.

Circadian clocks have evolved in most light-sensitive organisms, from unicellular organisms to mammals. Consequently, a myriad of biological functions exhibits circadian rhythmicity, from behavior to physiology, through tissue and cellular functions to subcellular processes. Circadian rhythms in intracellular organelles are an emerging and exciting research arena. We summarize herein the current literature for rhythmicity in major intracellular organelles in mammals. These include changes in the morphology, content, and functions of different intracellular organelles. While these data highlight the presence of rhythmicity in these organelles, a gap remains in our knowledge regarding the underlying molecular mechanisms and their functional significance. Finally, we discuss the importance and challenges faced by spatio-temporal studies on these organelles and speculate on the presence of oscillators in organelles and their potential mode of communication. As circadian biology has been and continues to be studied throughout temporal and spatial axes, circadian organelles appear to be the next frontier. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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