Motor proteins at the mitochondria–cytoskeleton interface

ABSTRACT Mitochondria are multifunctional organelles that not only produce energy for the cell, but are also important for cell signalling, apoptosis and many biosynthetic pathways. In most cell types, they form highly dynamic networks that are constantly remodelled through fission and fusion events, repositioned by motor-dependent transport and degraded when they become dysfunctional. Motor proteins and their tracks are key regulators of mitochondrial homeostasis, and in this Review, we discuss the diverse functions of the three classes of motor proteins associated with mitochondria – the actin-based myosins, as well as the microtubule-based kinesins and dynein. In addition, Miro and TRAK proteins act as adaptors that link kinesin-1 and dynein, as well as myosin of class XIX (MYO19), to mitochondria and coordinate microtubule- and actin-based motor activities. Here, we highlight the roles of motor proteins and motor-linked track dynamics in the transporting and docking of mitochondria, and emphasize their adaptations in specialized cells. Finally, we discuss how motor–cargo complexes mediate changes in mitochondrial morphology through fission and fusion, and how they modulate the turnover of damaged organelles via quality control pathways, such as mitophagy. Understanding the importance of motor proteins for mitochondrial homeostasis will help to elucidate the molecular basis of a number of human diseases.

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Interactions between Neisseria meningitidis and human cells that promote colonisation and disease

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399404008087 ◽

2004 ◽

Vol 6 (14) ◽

pp. 1-14 ◽

Cited By ~ 6

Author(s):

Anne Corbett ◽

Rachel Exley ◽

Sandrine Bourdoulous ◽

Christoph M. Tang

Keyword(s):

Cerebrospinal Fluid ◽

Bacterial Meningitis ◽

Neisseria Meningitidis ◽

Human Cell ◽

Molecular Basis ◽

Cell Types ◽

Cellular Level ◽

Human Cells ◽

Healthy Individuals ◽

Host Pathogen

Neisseria meningitidis is the leading cause of bacterial meningitis, a potentially fatal condition that particularly affects children. Multiple steps are involved during the pathogenesis of infection, including the colonisation of healthy individuals and invasion of the bacterium into the cerebrospinal fluid. The bacterium is capable of adhering to, and entering into, a range of human cell types, which facilitates its ability to cause disease. This article summarises the molecular basis of host–pathogen interactions at the cellular level during meningococcal carriage and disease.

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Cell-type specific calcium signalling in a Drosophila epithelium

Journal of Cell Science ◽

10.1242/jcs.110.15.1683 ◽

1997 ◽

Vol 110 (15) ◽

pp. 1683-1692 ◽

Cited By ~ 5

Author(s):

P. Rosay ◽

S.A. Davies ◽

Y. Yu ◽

A. Sozen ◽

K. Kaiser ◽

...

Keyword(s):

Nitric Oxide ◽

Critical Role ◽

Cell Signalling ◽

Calcium Signalling ◽

Malpighian Tubule ◽

Fluid Secretion ◽

Cell Types ◽

Cytosolic Calcium ◽

Atpase Inhibitor ◽

Principal Cells

Calcium is a ubiquitous second messenger that plays a critical role in both excitable and non-excitable cells. Calcium mobilisation in identified cell types within an intact renal epithelium, the Drosophila melanogaster Malpighian tubule, was studied by GAL4-directed expression of an aequorin transgene. CAP2b, a cardioactive neuropeptide that stimulates fluid secretion by a mechanism involving nitric oxide, causes a rapid, dose-dependent rise in cytosolic calcium in only a single, genetically-defined, set of 77 principal cells in the main (secretory) segment of the tubule. In the absence of external calcium, the CAP2b-induced calcium response is abolished. In Ca2+-free medium, the endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, elevates [Ca2+]i only in the smaller stellate cells, suggesting that principal cells do not contain a thapsigargin-sensitive intracellular pool. Assays for epithelial function confirm that calcium entry is essential for CAP2b to induce a physiological response in the whole organ. Furthermore, the data suggest a role for calcium signalling in the modulation of the nitric oxide signalling pathway in this epithelium. The GAL4-targeting system allows general application to studies of cell-signalling and pharmacology that does not rely on invasive or cytotoxic techniques.

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The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

AJP Cell Physiology ◽

10.1152/ajpcell.00471.2018 ◽

2019 ◽

Vol 317 (3) ◽

pp. C584-C599

Author(s):

Kurt D. Marshall ◽

Paula J. Klutho ◽

Lihui Song ◽

Maike Krenz ◽

Christopher P. Baines

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Kinase Domain ◽

Protective Role ◽

Mitochondrial Morphology ◽

Cyclophilin D ◽

Interacting Protein ◽

Mitochondrial Homeostasis

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

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Role of p90RSK in regulating the Crabtree effect: implications for cancer

Biochemical Society Transactions ◽

10.1042/bst20120277 ◽

2013 ◽

Vol 41 (1) ◽

pp. 124-126 ◽

Cited By ~ 9

Author(s):

Emily K. Redman ◽

Paul S. Brookes ◽

Marcin K. Karcz

Keyword(s):

Cancer Cell ◽

High Glucose ◽

Cell Metabolism ◽

Cell Signalling ◽

Cell Types ◽

Crabtree Effect ◽

Glucose Levels ◽

Mitogen Activated Protein ◽

Ribosomal S6 Kinase

High glucose inhibits mitochondrial respiration, known as the ‘Crabtree effect’, in cancer cells and possibly other cell types. The upstream pathways regulating this phenomenon are poorly understood. In diabetes, where glucose levels are elevated, the p90RSK (p90 ribosomal S6 kinase) has received much attention as a potential upstream mediator of the effects of high glucose. Evidence is also emerging that p90RSK may play a role in cancer cell signalling, although the role of p90RSK in regulating cancer cell metabolism is unclear. In the present paper, we provide an overview of the Crabtree effect and its relationship to mitochondrial metabolism. Furthermore, preliminary data are presented suggesting a role for p90RSK and its upstream components, the ERK (extracellular-signal-regulated kinase) family of MAPKs (mitogen-activated protein kinases), in the Crabtree effect.

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Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells

Cells ◽

10.3390/cells8101119 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1119 ◽

Cited By ~ 2

Author(s):

Hur ◽

Kang ◽

Kim ◽

Lee ◽

Kim ◽

...

Keyword(s):

Liver Fibrosis ◽

Serine Protease ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Mitochondrial Morphology ◽

Mice Model ◽

Hepatic Fibrogenesis ◽

Mitochondrial Homeostasis ◽

And Function ◽

Intracellular Energy

The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

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Identification and characterization of differentially active pools of type IIα phosphatidylinositol 4-kinase activity in unstimulated A431 cells

Biochemical Journal ◽

10.1042/bj20031212 ◽

2003 ◽

Vol 376 (2) ◽

pp. 497-503 ◽

Cited By ~ 25

Author(s):

Mark G. WAUGH ◽

Shane MINOGUE ◽

Deena BLUMENKRANTZ ◽

J. Simon ANDERSON ◽

J. Justin HSUAN

Keyword(s):

Kinase Activity ◽

Cell Signalling ◽

Cell Types ◽

Intrinsic Activity ◽

A431 Cells ◽

Cell Functions ◽

Subcellular Membrane ◽

Phosphatidylinositol Kinase ◽

Wide Range ◽

Phosphatidylinositol 4

The seven known polyphosphoinositides have been implicated in a wide range of regulated and constitutive cell functions, including cell-surface signalling, vesicle trafficking and cytoskeletal reorganization. In order to understand the spatial and temporal control of these diverse cell functions it is necessary to characterize the subcellular distribution of a wide variety of polyphosphoinositide synthesis and signalling events. The predominant phosphatidylinositol kinase activity in many mammalian cell types involves the synthesis of the signalling precursor, phosphatidylinositol 4-phosphate, in a reaction catalysed by the recently cloned PI4KIIα (type IIα phosphatidylinositol 4-kinase). However the regulation of this enzyme and the cellular distribution of its product in different organelles are very poorly understood. This report identifies the existence, in unstimulated cells, of two major subcellular membrane fractions, which contain PI4KIIα possessing different levels of intrinsic activity. Separation of these membranes from each other and from contaminating activities was achieved by density gradient ultracentrifugation at pH 11 in a specific detergent mixture in which both membrane fractions, but not other membranes, were insoluble. Kinetic comparison of the purified membrane fractions revealed a 4-fold difference in Km for phosphatidylinositol and a 3.5-fold difference in Vmax, thereby indicating a different mechanism of regulation to that described previously for agonist-stimulated cells. These marked differences in basal activity and the occurrence of this isozyme in multiple organelles emphasize the need to investigate cell signalling via PI4KIIα at the level of individual organelles rather than whole-cell lysates.

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Update on the Mechanisms of Liver Regeneration

Seminars in Liver Disease ◽

10.1055/s-0037-1601351 ◽

2017 ◽

Vol 37 (02) ◽

pp. 141-151 ◽

Cited By ~ 27

Author(s):

Morgan Preziosi ◽

Satdarshan Monga

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Signaling Pathways ◽

Surgical Resection ◽

Molecular Basis ◽

Cell Types ◽

Hepatic Cell ◽

Restoration Process

AbstractLiver possesses many critical functions such as synthesis, detoxification, and metabolism. It continually receives nutrient-rich blood from gut, which incidentally is also toxin-rich. That may be why liver is uniquely bestowed with a capacity to regenerate. A commonly studied procedure to understand the cellular and molecular basis of liver regeneration is that of surgical resection. Removal of two-thirds of the liver in rodents or patients instigates alterations in hepatic homeostasis, which are sensed by the deficient organ to drive the restoration process. Although the exact mechanisms that initiate regeneration are unknown, alterations in hemodynamics and metabolism have been suspected as important effectors. Key signaling pathways are activated that drive cell proliferation in various hepatic cell types through autocrine and paracrine mechanisms. Once the prehepatectomy mass is regained, the process of regeneration is adequately terminated. This review highlights recent discoveries in the cellular and molecular basis of liver regeneration.

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TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulator

10.1101/330993 ◽

2018 ◽

Cited By ~ 2

Author(s):

Ashutosh Kumar ◽

Rakesh Kumar Majhi ◽

Tusar Kanta Acharya ◽

Karl-Heinz Smalla ◽

Eckart D Gundelfinger ◽

...

Keyword(s):

Cell Types ◽

Mitochondrial Proteins ◽

Mitochondrial Morphology ◽

Oxidative Potential ◽

Mitochondrial Abnormalities ◽

Charcot Marie Tooth Disease ◽

Transport Chain ◽

Key Factor ◽

Function Regulator ◽

Tooth Disease

TRPV4 has been linked with the development of sensory defects, neuropathic pain, neurodegenerative disorders such as Charcot Marie Tooth disease and various muscular dystrophies. In all these cases mitochondrial abnormalities were tagged as cellular hallmarks and such abnormalities have been reported as key factor for the pathophysiological conditions. Mitochondria also have the unique ability to sense and regulate their own temperature. Here, we demonstrate that TRPV4, a thermosensitive ion channels, localizes to a subpopulation of mitochondria in various cell lines, in primary cells and also in sperm cells. Improper expression and/or function of TRPV4 induce several mitochondrial abnormalities such as low oxidative potential, high Ca2+-influx and changes in electron transport chain functions. TRPV4 is also involved in regulation of mitochondrial morphology, smoothness, and fusion-fission events. The C-terminal cytoplasmic region of TRPV4 can localize it to mitochondria and interacts with mitochondrial proteins including Hsp60, Mfn1 and Mfn2. Regulation of mitochondria by TRPV4 may contribute to previously uncharacterized mitochondria-specific functions observed in various cell types. This discovery may help to link TRPV4-mediated channelopathies with mitochondria-mediated diseases.

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Cytonemes in Tumourigenesis

10.32545/encyclopedia201912.0004.v1 ◽

2019 ◽

Author(s):

Marta Portela

Keyword(s):

Cancer Progression ◽

Tumour Progression ◽

Cell Signalling ◽

Cell Communication ◽

Cell Types ◽

Wing Disc ◽

Genetic Ablation ◽

The Past ◽

Tumoral Cell ◽

To Receive

Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories have emerged as a novel alternative for cell to cell communication that are involved in development, physiology, and disease. Several recent studies have shown that signalling pathways mediated by cytonemes during development, are essential for certain tumoral cell types progression. In Drosophila wing disc EGFR and RET tumour models, cytoneme formation is required to receive signals from the neighbouring cells. Genetic ablation of cytonemes prevents tumour progression, restores apico-basal polarity, and improves survival. Furthermore, cytonemes in the Drosophila glial cells are essential for glioblastoma progression as they alter Wg/Fz1 signalling between glia and neurons. Research on cytoneme formation, maintenance, and cell signalling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression.

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Quantitative Analysis of the Cardiac Phosphoproteome in Response to Acute β-Adrenergic Receptor Stimulation In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms222212584 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12584

Author(s):

Alican Güran ◽

Yanlong Ji ◽

Pan Fang ◽

Kuan-Ting Pan ◽

Henning Urlaub ◽

...

Keyword(s):

Mass Spectrometry ◽

Adrenergic Receptor ◽

Molecular Basis ◽

Cell Signalling ◽

Receptor Stimulation ◽

Stable Isotope Labelling ◽

Isotope Labelling ◽

Major Mechanism ◽

Signalling Network

β-adrenergic receptor (β-AR) stimulation represents a major mechanism of modulating cardiac output. In spite of its fundamental importance, its molecular basis on the level of cell signalling has not been characterised in detail yet. We employed mass spectrometry-based proteome and phosphoproteome analysis using SuperSILAC (spike-in stable isotope labelling by amino acids in cell culture) standardization to generate a comprehensive map of acute phosphoproteome changes in mice upon administration of isoprenaline (ISO), a synthetic β-AR agonist that targets both β1-AR and β2-AR subtypes. Our data describe 8597 quantitated phosphopeptides corresponding to 10,164 known and novel phospho-events from 2975 proteins. In total, 197 of these phospho-events showed significantly altered phosphorylation, indicating an intricate signalling network activated in response to β-AR stimulation. In addition, we unexpectedly detected significant cardiac expression and ISO-induced fragmentation of junctophilin-1, a junctophilin isoform hitherto only thought to be expressed in skeletal muscle. Data are available via ProteomeXchange with identifier PXD025569.

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