Seminars in Cell and Developmental Biology, Journal Year: 2019, Volume and Issue: 94, P. 59 - 65
Published: Jan. 30, 2019
Language: Английский
Mitochondrion, Journal Year: 2021, Volume and Issue: 59, P. 135 - 153
Published: April 23, 2021
Language: Английский
Citations
50
Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 297(4), P. 101174 - 101174
Published: Sept. 6, 2021
Mitochondrial Ca2+ uptake tailors the strength of stimulation plasma membrane phospholipase C–coupled receptors to that cellular bioenergetics. However, how by mitochondrial uniporter (MCU) shapes receptor-evoked interorganellar signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, subcellular imaging, and mathematical modeling show MCU a universal regulator intracellular across mammalian cell types. activity sustains cytosolic preventing Ca2+-dependent inactivation store-operated release–activated channels inhibiting extrusion. Paradoxically, knockout (MCU-KO) enhanced responses store depletion. Physiological agonist in MCU-KO cells led frequency oscillations, endoplasmic reticulum refilling, nuclear translocation factor for activated T transcription factors, proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data has dual counterbalancing functions at cytosol–mitochondria interface, whereby cell-specific MCU-dependent clearance buffering capacity mitochondria reciprocally regulate transfer during signaling. These findings highlight critical function not only acute but also shaping signals function. In addition their well-established role energy production metabolism, play pathways transcription, survival, (1Tait S.W. Green D.R. Mitochondria signalling.J. Cell Sci. 2012; 125: 807-815Crossref PubMed Scopus (252) Google Scholar, 2Chandel N.S. Evolution as organelles.Cell Metab. 2015; 22: 204-206Abstract Full Text PDF (261) Scholar). particular, are active participants (3Bagur R. Hajnoczky G. Intracellular Ca(2+) sensing: Its calcium homeostasis signaling.Mol. Cell. 2017; 66: 780-788Abstract (228) 4De Stefani D. Rizzuto Pozzan T. Enjoy trip: Calcium back forth.Annu. Rev. Biochem. 2016; 85: 161-192Crossref 5Finkel Menazza S. Holmström K.M. Parks R.J. Liu J. Sun Pan X. Murphy E. The ins outs calcium.Circ. Res. 116: 1810-1819Crossref (124) 6Hempel N. Trebak M. Crosstalk between reactive oxygen species cancer.Cell Calcium. 63: 70-96Crossref (98) 7Kamer K.J. Mootha V.K. molecular era uniporter.Nat. Mol. Biol. 16: 545-553Crossref (191) 8Pathak signaling.Pharmacol. Ther. 2018; 192: 112-123Crossref (64) uptake, which driven steep voltage gradient inner membrane, occurs through protein complex containing pore-forming (9Baughman J.M. Perocchi F. Girgis H.S. Plovanich Belcher-Timme C.A. Sancak Y. Bao X.R. Strittmatter L. Goldberger O. Bogorad R.L. Koteliansky V. Integrative genomics identifies an essential component uniporter.Nature. 2011; 476: 341-345Crossref (1207) 10De Raffaello A. Teardo Szabó I. A forty-kilodalton 336-340Crossref (1233) forms Ca2+-selective tetrameric channel regulated gate-keeping Ca2+-binding MICU1/2 dimers (11Csordas Golenar Seifert E.L. Kamer Moffat C. Weaver Perez S.F. Adijanto MICU1 controls both threshold cooperative activation Ca(2)(+) uniporter.Cell 2013; 17: 976-987Abstract (312) 12Mallilankaraman K. Doonan P. Cardenas Chandramoorthy H.C. Muller Miller Hoffman N.E. Gandhirajan R.K. Molgo Birnbaum M.J. Rothberg B.S. Mak D.O. Foskett J.K. Madesh gatekeeper MCU-mediated regulates survival.Cell. 151: 630-644Abstract (405) 13Payne Hoff H. Roskowski MICU2 restricts spatial crosstalk InsP3R regulating gain MICU1-mediated inhibition MCU.Cell Rep. 21: 3141-3154Abstract (45) 14Kamer Grabarek Z. High-affinity binding MICU1-MICU2 serves on-off switch uniporter.EMBO 18: 1397-1411Crossref (78) 15Perocchi Gohil V.M. McCombs J.E. Palmer A.E. encodes EF hand required uptake.Nature. 2010; 467: 291-296Crossref (606) 16Kamer Jiang W. Kaushik Crystal structure comparison with reveal insights into gating mechanism.Proc. Natl. Acad. U. 2019; 3546Crossref (25) keep closed under resting levels free Ca2+. Increased concentration vicinity EF-hand domains disinhibits enhances (13Payne extrusion from matrix cytosol independent transporters, include Na+/Ca2+ exchanger (NCLX) (17Palty Hershfinkel Sekler Molecular identity functional properties exchanger.J. Chem. 287: 31650-31657Abstract (43) Scholar) possibly Ca2+/H+ Letm1 (18Jiang Zhao Clapham D.E. Genome-wide RNAi screen antiporter.Science. 2009; 326: 144-147Crossref (368) gatekeeping relieved when high (above ∼1.3 μM above 500 nM present Scholar), see (14Kamer where calculated Kd ∼650 nM). As such, thought take place specialized microdomains concentrations high. Such mitochondria-associated membranes (MAMs) (ER) within 10 30 nm outer transferred closely apposed (IP3R) ER (19Csordas Renken Varnai Walter Buttle K.F. Balla Mannella Structural features significance physical linkage mitochondria.J. 2006; 174: 915-921Crossref (885) Activation (PM) couple isoforms C hormones, neurotransmitters, growth factors causes breakdown membrane-associated phosphatidylinositol-4,5-bisphosphate two second messengers: membrane-bound diacylglycerol diffusible IP3 (20Berridge inositol trisphosphate/calcium pathway health disease.Physiol. 96: 1261-1296Crossref (279) IP3R located Upon depletion, ER-resident stromal interaction molecules 1 2 (STIM1/2) undergo conformational change move ER-PM junctional spaces they form puncta activate Orai mediating highly Ca2+-selective, store-operated, (CRAC) current (21Prakriya Lewis R.S. Store-operated channels.Physiol. 95: 1383-1436Crossref (634) 22Trebak Kinet J.P. signalling cells.Nat. Immunol. 19: 154-169Crossref (121) 23Trebak Putney Jr., J.W. ORAI channels.Physiology (Bethesda). 32: 332-342PubMed Under conditions low agonists believed represent physiological stimulation, manifest regenerative result cycles release concomitant bursts CRAC activities that, depending on type, can either directly sustain oscillations or replenish depleted stores IP3R-driven (24Dupont Combettes Bird G.S. oscillations.Cold Spring Harb. Perspect. 3a004226Crossref (170) 25Sneyd Han Wang Chen Yang Tanimura Sanderson Kirk Yule D.I. On dynamical oscillations.Proc. 114: 1456Crossref (53) 26Dolmetsch R.E. Signaling depletion-activated generates [Ca2+]i lymphocytes.J. Gen. Physiol. 1994; 103: 365-388Crossref (151) Local entry Orai/CRAC leads (NFAT) (27Gwack Feske Srikanth Hogan P.G. Rao Signalling transcription: NFAT lymphocytes.Cell 2007; 42: 145-156Crossref (239) programs control various functions, including proliferation metabolism (28Vaeth immune function: New frontiers abiding trooper.F1000Res. 7: 260Crossref (65) 29Vaeth Maus Klein-Hessling Freinkman Eckstein Cameron Turvey S.E. Serfling Berberich-Siebelt Possemato clonal expansion metabolic reprogramming.Immunity. 47: 664-679.e666Abstract (111) enters accumulates side PM, it mediates several feedback mechanisms. First, there fast (CDI) involves inhibitory sites few nanometers mouth (30Mullins F.M. domain STIM1 functionally coupled Orai1 pore enable inactivation.J. 147: 153-164Crossref (36) 31Mullins Yen residues independently calmodulin.J. 137-152Crossref (37) 32Zhang Pathak Yoast Emrich Xin Nwokonko R.M. Johnson Wu Delierneux Gueguinou Hempel Gill D.L. calcium/cAMP loop ORAI1 drives shape induction.Nat. Commun. 10: 1971Crossref (41) 33Zweifach Rapid (ICRAC) due local feedback.J. 1995; 105: 209-226Crossref (327) locate 100 because size, would be presumably excluded tight span ∼10 25 STIM coaggregate. Therefore, unlikely affect CDI any meaningful way. Second, slow triggered refilling (34Zweifach Slow calcium-dependent current. Store-dependent -independent mechanisms.J. 270: 14445-14451Abstract (225) reversal mitochondria. Third, another (e.g., presence thapsigargin) This store-independent mediated ∼100 more was proposed Ca2+-calmodulin (CaM)-mediated dissociation STIM1–Orai1 complexes (35Li Fu Kang Su X.C. Shen Calmodulin dissociates STIM1-Orai1 oligomers.Nat. 8: 1042Crossref (33) latter could prevented distant microdomain CaM located. Indeed, previous studies pre-dating discovery STIM–Orai have drugs such carbonyl cyanide m-chlorophenylhydrazone (CCCP) antimycin A1, inhibit respiration depolarizing its propose buffer alleviate (SOCE) Jurkat primary (36Hoth Button D.C. calcium-channel gating: mechanism sustained transcriptional lymphocytes.Proc. 2000; 97: 10607-10612Crossref (227) 37Hoth Fanger C.M. regulation 1997; 137: 633-648Crossref (455) recent study utilized knockdown siRNA rat basophilic leukemia (RBL) suggested specifically sustaining IP3R, channels, agonist-evoked (38Samanta Douglas Parekh A.B. supports cytoplasmic expression response stimulation.PLoS One. 2014; 9e101188Crossref (61) investigated cytosolic, ER, dynamics using arsenal lines different tissues. We produce clones cultured Cre-LoxP system generate populations tissue-specific mice. despite promoting enhancing extrusion, deletion passive affecting IP3R-mediated puffs. increased B-lymphocyte proliferation. Mathematical consistent important fine-tunes provide Despite limiting paradoxical enhancement upon stimulation. Thus, inability "allocated share" absence offsets effects net interface. enhance near PM increase "Ca2+ sink" effect reciprocal performed six tissues (Fig. 1). seventh line (HeLa) corresponding clone were kindly provided Dr Suresh Joseph (Thomas Jefferson University) S1). human HeLa, embryonic kidney (HEK293), colorectal cancer HCT116 DLD1, cells, (RBL-1) mast mouse A20 B cells. clean background analyze To potential off-target KO, studied each (except HeLa obtained one clone). identified; validated genomic sequencing, Western blot, measurements; assayed parallel parental controls. Absence documented blot 1, A, C, E, G, I, K). Functional simultaneous fluorescence measurements permeabilized S2). bolus bath resulted rapid did occur demonstrating abrogated predominant receptor-activated all seven nonexcitable considered herein SOCE pathway, biophysically manifests encoded STIM1/2 Orai1/2/3 proteins. maximally SOCE, irreversibly blocked sarcoplasmic/ER ATPase (SERCA) thapsigargin (Tg; μM), depletion (recorded Ca2+-free solutions) mM extracellular B, D, F, H, J, L). Surprising, use this protocol revealed significant apparent lines, exception HEK293 some runs significantly averaged 1B; Fig. 2A). notable difference other will addressed further below. blots showed no S3). Quantitative PCR analysis compensatory up/downregulation five proteins S4). Previous reports abrogation ability Ca2+, dissipation protonophore blockade III V electron transport chain Antimycin A1 oligomycin, (37Hoth currents inhibited these drugs, recorded perforated patch-clamp technique whole-cell pipette solutions relatively (1.2 EGTA) metabolites promote energized healthy turn limits SOCE. HEK293, Jurkat, RBL-1 counterparts tested 5 trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP) seen Figure 2, A–C, added after initiated, FCCP counterparts. 2B) 2C) slower than preceded transient reflecting bigger rate similar wildtype 2A), suggesting contribution reservoir compared Addition ionomycin (red arrow; B) remaining thapsigargin-independent (presumably mitochondria) small subsequently (blue arrow) confirm maximal Fura2 signal equal Overall, argue cannot explained simply lack MCU. One recurring observation our recordings decline steady-state plateaus C), inhibits ATPase–mediated shown previously (39Quintana Pasche Junker Al-Ansary Rieger Kummerow Nunez Villalobos Meraner Becherer Rettig Niemeyer B.A. Hoth immunological synapse: How pumps efficient T-cell activation.EMBO 30: 3895-3912Crossref (146) Gd3+ faster 3, D).Figure 3MCU-KO (A (C D) stimulated Tg followed restoration determine magnitude block assess slope reported statistically (B D). Statistical determined Kruskal–Wallis one-way ANOVA multiple comparisons ∗∗∗∗p < 0.0001. Cytosolic traces C) ±SEM n = 82 178 individual MCU, uniporter.View Large Image ViewerDownload Hi-res image Download (PPT) then sought whether patch clamp technique. chose record widely largest native currents, namely, 20 switches divalent-free Na+ larger size. measured conditions. first condition uses solution (1 includes empty contains cocktail mitochondria-energizing (see Methods) CDI. very strong (50 BAPTA) negate currents. Native weak 4). accurately if alters CDI, established preincubated ICRAC introduction EGTA, 0.66 Scholar); Experimen
Language: Английский
Citations
46
Cell Calcium, Journal Year: 2023, Volume and Issue: 117, P. 102817 - 102817
Published: Nov. 4, 2023
Language: Английский
Citations
21
International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2229 - 2229
Published: Jan. 23, 2023
Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin protein and a properly functioning dystrophin-associated complex (DAPC) in muscle cells. DAPC components act as molecular scaffolds coordinating assembly various signaling molecules including ion channels. DMD shows significant change channels sarcolemma intracellular organelles and, above all, sarcoplasmic reticulum mitochondria regulating homeostasis, which necessary for correct excitation relaxation muscles. This review devoted to analysis current data on changes structure, functioning, regulation activity striated muscles their contribution disruption function development pathology. We note prospects therapy based targeting correction alleviation pathology, problems that arise interpretation obtained model dystrophin-deficient objects.
Language: Английский
Citations
20
Seminars in Cell and Developmental Biology, Journal Year: 2019, Volume and Issue: 94, P. 59 - 65
Published: Jan. 30, 2019
Language: Английский
Citations
48