Intracellular Energetic Units regulate metabolism in cardiac cells

Saks, Valdur; Kuznetsov, Andrey V.; González‐Granillo, Marcela; Tepp, Kersti; Timohhina, Natalja; Karu-Varikmaa, Minna; Käämbre, Tuuli; Santos, Pierre Dos; Boucher, François; Guzun, Rita

doi:10.1016/j.yjmcc.2011.07.015

Cited by 53 publications

(84 citation statements)

References 175 publications

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“…Depolymerisation of tubulin in cancer cells lacking MtCK induces a decrease in mitochondrial membrane potential due to increased restriction of ATP and ADP diffusion at the level of MOM and the absence of a compensating CK/PCr phosphoryl transfer network (Maldonado et al 2010). In cardiomyocytes, contrary to cancer cells, the restricted diffusion of adenine nucleotides at the level of MOM favors the compartmentalized energy transfer through the CK/PCr network (Saks et al 2012). Thus, functional coupling of the MtCK reaction to ATP synthesis via ANT mainly occurs under conditions of restricted ATP/ADP diffusion at the level of MOM.…”

Section: Proteolipid Complexes Involving Mitochondrial Creatine Kinasmentioning

confidence: 99%

“…The functional coupling of MtCK to ANT and ATP synthesis may occur within a supra-macromolecular complex along the cristae membranes where MtCK occurs together with the ATP synthasome consisting of ATP synthase, inorganic phosphate carrier (PIC) and ANT (Chen et al 2004). The role of MtCK within this mitochondrial interactosome is to separate energy fluxes from the intracellular energy signals and to amplify these signals due to the intramitochondrial recycling of ADP Saks et al 2012).…”

Section: Proteolipid Complexes Involving Mitochondrial Creatine Kinasmentioning

confidence: 99%

“…These energetic microcompartments associate sites of ATP (or GTP) generation with the corresponding sites of consumption, and this can occur at different scales. They may correspond to cellular domains with preferential directions of diffusion, such as in so-called intracellular energetic units (Saks et al 2001;Seppet et al 2005;Saks et al 2012), or represent large multi-protein or proteo-lipid complexes where more or less tight metabolite channeling can occur (Ovadi and Srere 2000;Schlattner and Wallimann 2013).…”

mentioning

confidence: 99%

“…The CK/PCr shuttle is particularly important for large and polar cells with high and/or fluctuating energy demands such as skeletal and heart muscle cells, or many cell types in the brain, but may occur in any cell type expressing CK. Further exhaustive information on various aspects of the CK/PCr system can be found in previous reviews (Bessman and Carpenter 1985;Bessman and Geiger 1981;Ellington 2001;McLeish and Kenyon 2005;Saks et al 2006Saks et al , 2007Saks et al , 2012Schlattner et al 2006a;Wallimann et al 1992Wallimann et al , 2007.…”

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confidence: 99%

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Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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There is an increasing body of evidence for local circuits of ATP generation and consumption that are largely independent of global cellular ATP levels. These are mostly based on the formation of multiprotein(-lipid) complexes and diffusion limitations existing in cells at different levels of organization, e.g., due to the viscosity of the cytosolic medium, macromolecular crowding, multiple and bulky intracellular structures, or controlled permeability across membranes. Enzymes generating ATP or GTP are found associated with ATPases and GTPases enabling the direct fueling of these energy-dependent processes, and thereby implying that it is the local and not the global concentration of high-energy metabolites that is functionally relevant. A paradigm for such microcompartmentation is creatine kinase (CK). Cytosolic and mitochondrial isoforms of CK constitute a well established energy buffering and shuttling system whose functions are very much based on local association of CK isoforms with ATP-providing and ATP-consuming processes. Here we review current knowledge on the subcellular localization and direct protein and lipid interactions of CK isoforms, in particular about cytosolic brain-type CK (BCK) much less is known compared to muscle-type CK (MCK). We further present novel data on BCK, based on three different experimental approaches: (1) co-purification experiments, suggesting association of BCK with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively; (2) yeast-two-hybrid analysis using cytosolic split-protein assays and the identifying membrane proteins VAMP2, VAMP3 and JWA as putative BCK interaction partners; and (3) phosphorylation experiments, showing that the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate BCK at serine 6 to trigger BCK localization at the ER, in close vicinity of the highly energy-demanding Ca(2+) ATPase pump. Thus, membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations.

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Section: Proteolipid Complexes Involving Mitochondrial Creatine Kinasmentioning

confidence: 99%

Section: Proteolipid Complexes Involving Mitochondrial Creatine Kinasmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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“…Several groups have hypothesized that the MT cytoskeleton contributes to intracellular metabolic regulation (10,11), raising the possibility that docetaxel treatment will be more effective when combined with metabolic inhibitors. In this study we examined whether MT-targeting drugs (including MT stabilizing drugs docetaxel and paclitaxel, and a MT depolymerizing drug, nocodazole) act synergistically with metabolic inhibitors, metformin or 2-DG, to inhibit proliferation and cause cell death in cell lines derived from prostate cancers.…”

Section: Introductionmentioning

confidence: 99%

Microtubule Control of Metabolism in Prostate Cancer

Cassimeris¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe current standard chemotherapy treatment for metastatic castrate-resistant prostate cancer is the microtubule-stabilizing drug, docetaxel, but the median increase in survival is limited to several months. One avenue for improved treatment outcome is to find agents that increase cell death when combined with docetaxel.Here we tested whether two metabolic inhibitors, metformin or 2-deoxy-glucose, function synergistically with docetaxel to block prostate cancer cell proliferation. LNCaP and PC-3 prostate cancer cell lines were incubated in drugs targeting the microtubule cytoskeleton (docetaxel, paclitaxel, or nocodazole) singly, or in combination with metabolic inhibitors (metformin or 2-deoxy-glucose). Microtubule-targeted drugs, which either stabilize or destabilize microtubules, acted synergistically with either metformin or 2-deoxy-glucose to block cell proliferation and cause cell death in both prostate cancer cell lines tested. Synergy was consistently calculated at the ED50 for each drug, but for many drug combinations, the combination index shifted toward antagonism at higher drug doses. Microtubule stabilizers (docetaxel, paclitaxel) showed greater synergy than did a microtubule destabilizer (nocodazole) when combined with either of the metabolic inhibitor tested. The more-thanadditive cell killing measured in two commonly used prostate cancer lines treated with a mixture of microtubule-targeted drugs and metabolic inhibitors indicates that these drug combinations could provide more effective tumor cell killing than either drug alone. SUBJECT TERMSNone provided. IntroductionProstate cancer is the second leading cause of cancer deaths for men in the United States (American Cancer Society, 2013 statistics). Although often cured by surgery or radiation treatment, for many patients the disease progresses from one responsive to androgen removal to one where cancer cells have become androgen insensitive, the latter termed metastatic castrate-resis...

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Mitochondrial network energetics in the heart

Aon

Cortassa

2012

WIREs Mechanisms of Disease

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At the core of eukaryotic aerobic life, mitochondria function like “hubs” in the web of energetic and redox processes in cells. In the heart, these networks - extending beyond the complex connectivity of biochemical circuit diagrams and apparent morphology - exhibit collective dynamics spanning several spatio-temporal levels of organization, from the cell, to the tissue, and the organ. The network function of mitochondria, i.e. mitochondrial network energetics, represents an advantageous behaviour. Its coordinated action, under normal physiology, provides robustness despite failure in a few nodes, and improves energy supply toward a swiftly changing demand. Extensive diffuse loops, encompassing mitochondrialcytoplasmic reaction/transport networks, control and regulate energy supply and demand in the heart. Under severe energy crises, the network behaviour of mitochondria and associated glycolytic and other metabolic networks collapse, thereby triggering fatal arrhythmias.

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Intracellular Energetic Units regulate metabolism in cardiac cells

Cited by 53 publications

References 175 publications

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

Microtubule Control of Metabolism in Prostate Cancer

Mitochondrial network energetics in the heart

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