Abstract
Research over the last decade has extended the prevailing view of cell mitochondrial function well beyond its critical bioenergetic role in supplying ATP. Recently, it has been recognized that the mitochondria play a critical role in cell regulatory and signaling events, in the responses of cells to a multiplicity of physiological and genetic stresses, inter-organelle communication, cell proliferation and cell death. Nevertheless, a broad-based review on mitochondrial signaling is not presently available. To bridge that gap, this review examines the perspective of mitochondria as the receiver integrator and transmitter of signals, dissecting the multiple and interrelated signaling pathways at both the molecular and biochemical levels with particular focus on nuclear and cytoplasmic factors, fundamentally involved in the shaping of the organelles' responses. We examine evidence that the mitochondria act as a dynamic receiver and integrator of numerous translocated signaling proteins (including protein kinases and transcription factors), regulatory Ca2+ fluxes and membrane phospholipids as well the transmission of mitochondrial-generated oxidative stress and energy-related signaling. Novel experimental approaches studying mitochondrial signaling including cell studies using metabolic inhibitors and genetic stresses (e.g. mtDNA depletion) are discussed. While there is abundant interest and information concerning its integral role to apoptosis, mitochondrial signaling also plays a fundamental role in proliferative pathways, nutrient sensing, inter-organellar cross-talk and in the responses of cells to metabolic transition and physiological stresses which remain relatively unexplored. (Mol Cell Biochem 262: 1–16, 2004)
Similar content being viewed by others
References
Hatefi Y: The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54: 1015–1069, 1985
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG: Sequence and organization of human mitochondrial genome. Nature 290: 457–465, 1981
Attardi G, Schatz G: Biogenesis of mitochondria. Annu Rev Cell Biol 4:289–333, 1988
Hood DA: Contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90: 1137–1157, 20
Totland GK, Madsen L, Klementsen B, Vaagenes H, Kryvi H, Froyland L, Hexeberg S, Berge RK: Proliferation of mitochondria and gene expression of carnitine palmitoyltransferase and fatty acyl-CoA oxidase in rat skeletal muscle, heart and liver by hypolipidemic fatty acids. Biol Cell 92: 317–329, 2000
Lundgren B, Meijer J, DePierre JW: Induction of cytosolic and microsomal epoxide hydrolases and proliferation of peroxisomes and mitochondria in mouse liver after dietary exposure to p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Biochem Pharmacol 36: 815–821, 1987
Weber K, Bruck P, Mikes Z, Kupper JH, Klingenspor M, Wiesner RJ: Glucocorticoid hormone stimulates mitochondrial biogenesis specifi-cally in skeletal muscle. Endocrinology 143: 177–184, 2002
Williams RS, Garcia-Moll M, Mellor J, Salmons S, Harlan W: Adaptation of skeletal muscle to increased contractile activity. J Biol Chem 262: 2764–2767, 1987
Nelson BD: Thyroid hormone regulation of mitochondrial function: Comments on the mechanism of signal transduction. Biochim Biophys Acta 1018: 275–277, 1990
Xia Y, Buja LM, Scarpulla RC, McMillin JB: Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci USA 94:11399–11404, 1997
Bogenhagen D, Clayton DA: The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells: Quantitative isolation of mitochondrial deoxyribonucleic acid. J Biol Chem 249: 7991–7995, 1974
Shadel GS, Clayton DA: Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem 66: 409–435, 1997
Kadenbach B, Stroh A, Becker A, Eckerskorn C, Lottspeich F: Tissueand species-specific expression of cytochrome coxidase isozymes in vertebrates. Biochim Biophys Acta 1015: 368–372, 1990
Lenka N, Vijayasarathy C, Mullick J, Avadhani NG: Structural organization and transcription regulation of nuclear genes encoding the mammalian cytochrome coxidase complex. Prog Nucleic Acid Res Mol Biol 61: 309–344, 1998
Boveris A, Chance B: The mitochondrial generation of hydrogen peroxide. Biochem J 134: 707–716, 1973
McLennan HR, Degli Esposti M: The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomembr 32: 153–162, 2000
Turrens JF: Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17: 3–8, 1997
Raha S, Robinson BH: Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25: 502–508, 2000
Richter C: Reactive oxygen and DNA damage in mitochondria. Mutat Res 275: 249–255, 1992
Richter C, Park JW, Ames BN: Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 85:6465–6467, 1988
Oldenburg O, Cohen MV, Yellon DM, Downey JM: Mitochondrial K(ATP) channels: Role in cardioprotection. Cardiovasc Res 55: 429—437, 2002
van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P: Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun 304: 487–497. 2003
Kroemer G: Mitochondrial control of apoptosis: An introduction. Biochem Biophys Res Commun 304: 433–435, 2003
Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD: Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331–342, 2002
Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G: The permeability transition pore complex: A target for apoptosis regulation by caspases and Bcl-2 related proteins. J Exp Med 187: 1261–1271, 1998
Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B: The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366: 177–196, 1998
Schinder AF, Olson EC, Spitzer NC, Montal M: Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J NeuroSci 16: 6125–6133, 1996
Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G: Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281: 2027–2031, 1998
Gilde AJ, van der Lee KA, Willemsen PH, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, van Bilsen M: Peroxisome proliferatoractivated receptor PPAR aand PPAR ß/dbut not PPAR ?, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 92: 518–524, 2003
Goffart S, Wiesner RJ: Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis. Exp Physiol 88: 33–40, 2003
Scarpulla RC: Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta 1576: 1–14, 2002
Barger PM, Kelly DP: PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10: 238–245, 2000
Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly D:. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106: 847—856, 2000
Wu H, Kanatous SB, Thurmond FA, GallardoT, Isotani E, Bassel-Duby R, Williams RS: Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296: 349–352, 2002.
Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, Lin B, Chen G, Lu J, Lin F, Xie Z, Fontana JA, Reed JC, Zhang X: Cytochrome crelease and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289: 1159–1164, 2000
Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P: Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: Enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection. Circ Res 90: 390–397, 2002
Baines CP, Song CX, ZhengYT, Wang GW, Zhang J, Wang OL, GuoY, Bolli R, Cardwell EM, Ping P: Protein kinase Cepsilon interacts with 14 and inhibits the permeability transition pore in cardiac mitochondria. Circ Res 92: 873–880, 2003
Majumder PK, Mishra NC, Sun X, Bharti A, Kharbanda S, Saxena S, Kufe D: Targeting of protein kinase C delta to mitochondria in the oxidative stress response. Cell Growth Differ 12: 465–470, 2001
Sumitomo M, Ohba M, Asakuma J, Asano T, Kuroki T, Asano T, Hayakawa M: Protein kinase C delta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J Clin Invest 109: 827–836, 2002
Caruso M, Maitan MA, Bifulco G, Miele C, Vigliotta G, Oriente F, Formisano P, Beguinot F: Activation and mitochondrial translocation of protein kinase C delta are necessary for insulin stimulation of pyruvate dehydrogenase complex activity in muscle and liver cells. J Biol Chem 276: 45088–45097, 2001
Majumder PK, Pandey P, Sun X, Cheng K, Datta R, Saxena S, Kharbanda S, Kufe D: Mitochondrial translocation of protein kinase C delta in phorbol ester-induced cytochrome C release and apoptosis. J Biol Chem 275: 21793–21796, 2000
Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Munshi N, Kharbanda S, Anderson KC: JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J Biol Chem 278: 17593–17596, 2003
Ginsberg MD, Feliciello A, Jones JK, Avvedimento EV, Gottesman ME: PKA-dependent binding of mRNA to the mitochondrial AKAP121 protein. J Mol Biol 327: 885–897, 2003
Affaitati A, Cardone L, de Cristofaro T, Carlucci A, Ginsberg MD, Varrone S, Gottesman ME, Avvedimento EV, Feliciello A: Essential role of A-kinase anchor protein 121 for cAMP signaling to mitochondria. J Biol Chem 278: 4286–4294, 2003
Papa S: The NDUFS4 nuclear gene of complex I of mitochondria and the cAMP cascade. Biochim Biophys Acta 1555: 147–153, 2002
Lee I, Bender E, Kadenbach B: Control of mitochondrial membrane potential and ROS formation by reversible phosphorylation of cytochrome C oxidase. Mol Cell Biochem 234, 235: 63–70, 2002
Salvi M, Brunati AM, Bordin L, La Rocca N, Clari G, Toninello A: Characterization and location of Src-dependent tyrosine phosphorylation in rat brain mitochondria. Biochim Biophys Acta 1589: 181–195. 2002
Yuryev A, Ono M, Goff SA, Macaluso F, Wennogle LP: Isoformspecific localization of A-RAF in mitochondria. Mol Cell Biol 20: 4870–4878, 2000
Le Mellay V, Troppmair J, Benz R, Rapp UR: Negative regulation of mitochondrial VDAC channels by C-Raf kinase. BMC Cell Biol 3: 14, 2002
Thomson M: Evidence of undiscovered cell regulatory mechanisms: Phospho-proteins and protein kinases in mitochondria. Cell Mol Life Sci 59: 213–219, 2002
Schulenberg B, Aggeler R, Beechem JM, Capaldi RA, Patton WF: Analysis of steady-state protein phosphorylation in mitochondria using a novel fluorescent phosphosensor dye. J Biol Chem 278: 27251—27255, 2003
Bykova NV, Egsgaard H, Moller IM: Identification of 14 newphosphoproteins involved in important plant mitochondrial processes. FEBS Lett 540: 141–146, 2003
Hojlund K, Wrzesinski K, Larsen PM, Fey SJ, Roepstorff P, Handberg A, Dela F, Vinten J, McCormack JG, Reynet C, Beck-Nielsen H: Proteome analysis reveals phosphorylation of ATP synthase-subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 278: 10436–10442, 2003
He H, Chen M, Scheffler NK, GibsonBW, Spremulli LL, Gottlieb RA: Phosphorylation of mitochondrial elongation factor Tu in ischemic myocardium: Basis for chloramphenicol-mediated cardioprotection. Circ Res 89: 461–467, 2001
Cammarota M, Paratcha G, Bevilaqua LR, Levi de Stein M, Lopez M, Pellegrino de Iraldi A, Izquierdo I, Medina JH: Cyclic AMP-responsive element binding protein in brain mitochondria. J Neurochem 72: 2272—2277, 1999
Cogswell PC, Kashatus DF, Keifer JA, Guttridge DC, Reuther JY, Bristow C, Roy S, Nicholson DW, Baldwin AS: NF-kappa B and I kappa B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-kappa B. J Biol Chem 278: 2963–2968, 2003
Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Wiesner RJ, Cabello G, Wrutniak C: A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19: 7913–7924, 1999
Davis PJ, Davis FB: Nongenomic actions of thyroid hormone. Thyroid 6: 497–504, 1996
Weber K, Bruck P, Mikes Z, Kupper JH, Klingenspor M, Wiesner RJ: Glucocorticoid hormone stimulates mitochondrial biogenesis specifi-cally in skeletal muscle. Endocrinology 143: 177–184, 2002
Casas F, Daury L, Grandemange S, Busson M, Seyer P, Hatier R, Carazo A, Cabello G, Wrutniak-Cabello C: Endocrine regulation of mitochondrial activity: Involvement of truncated RXRalpha and c-Erb Aalpha1 proteins. FASEB J 17: 426–436, 2003
Casas F, Domenjoud L, Rochard P, Hatier R, Rodier A, Daury L, Bianchi A, Kremarik-Bouillaud P, Becuwe P, Keller J, Schohn H, Wrutniak-Cabello C, Cabello G, Dauca M: A 45 kDa protein related to PPAR-2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett 478: 4–8, 2000
Elfering SL, Sarkela TM, Giulivi C: Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem 277: 38079–38086, 2002
RioboNA, Melani M, Sanjuan N, Fiszman ML, Gravielle MC, Carreras MC, Cadenas E, Poderoso JJ: The modulation of mitochondrial nitricoxide synthase activity in rat brain development. J Biol Chem 277: 42447–42455, 2002
Carreras MC, Peralta JG, Converso DP, Finocchietto PV, Rebagliati I, Zaninovich AA, Poderoso JJ: Modulation of liver mitochondrial NOS is implicated in thyroid-dependent regulation of O2 uptake. Am J Physiol Heart Circ Physiol 281: H2282–H2288, 2001
Lacza Z, Puskar M, Figueroa JP, Zhang J, Rajapakse N, Busija DW: Mitochondrial nitric oxide synthase is constitutively active and is functionally upregulated in hypoxia. Free Radic Biol Med 31: 1609–1615, 2001
Escames G, Leon J, Macias M, Khaldy H, Acuna-Castroviejo D: Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 17: 932–934, 2003
Brodsky SV, Gao S, Li H, Goligorsky MS: Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol 283: H2130–H2139, 2002
Ghafourifar P, Mitochondrial nitricoxide synthase stimulation causes cytochrome C release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation. J Biol Chem 274: 31185–31188, 1999
Bustamante J, Bersier G, Badin RA, Cymeryng C, Parodi A, Boveris A: Sequential NO production by mitochondria and endoplasmic reticulum during induced apoptosis. Nitric Oxide 6: 333–341, 2002
Ghafourifar P, Schenk U, Klein SD, Richter C: Mitochondrial nitric-oxide synthase stimulation causes cytochrome C release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation. J Biol Chem 274: 31185–31188, 1999
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590, 2003
Sansome C, Zaika A, Marchenko ND, Moll UM: Hypoxia death stimulus induces translocation of p53 protein to mitochondria. Detection by immunofluorescence on whole cells. FEBS Lett 488: 110–115, 2001 15
Marchenko ND, Zaika A, Moll UM: Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem 275: 16202–16212, 2000
Duchen M: Contributions of mitochondria to animal physiology: From homeostatic sensor to calcium signalling and cell death. J Physiology 516: 1–17, 1999
McCormack JG, Halestrap AP, Denton RM: Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70: 391–425, 1990
Pacher P, Hajnoczky G: Propagation of the apoptotic signal by mitochondrial waves}. EMBO J 20: 4107–4121, 2001
Robb-Gaspers LD, Burnett P, Rutter GA, Denton RM, Rizzuto R, Thomas AP: Integrating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J 17: 4987–5000, 1998
Denton RM, McCormack JG: The calcium sensitive dehydrogenases of vertebrate mitochondria. Cell Calcium 7: 377–386, 1986
Das AM, Harris DA: Control of mitochondrial ATP synthase in rat cardiomyocytes: Effects of thyroid hormone. Biochim Biophys Acta 1096: 284–290, 1991
Jouaville LS, Ischas F, Mazat JP: Modulation of cell calcium signals by mitochondria. Mol Cell Biochem 184: 371–376, 1998
Rutter GA, Rizzuto R: Regulation of mitochondrial metabolism by ER Ca2+ release: An intimate connection. Trends 25: 215–221, 2000
Rizzuto R: Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280: 1763–1766, 1998
Csordas G, Thomas AP, HajnoczkyG: Calcium signal transmission between ryanodine receptors and mitochondria in cardiac muscle. Trends Cardiovasc Med 11: 269–275, 2001
Gunter TE, Gunter KK: Uptake of calcium by mitochondria: Transport and possible function. IUBMB Life 52: 197–204, 2001
Buntinas L, Gunter KK, Sparagna GC, Gunter TE: The rapid mode of calcium uptake into heart mitochondria (RaM): Comparison to RaM in liver mitochondria. Biochim Biophys Acta 1504: 248–261, 2001
Crompton M, Costi A, Hayat L. Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J 245: 915–918, 1987
Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R: Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159: 613–624, 2002
Hajnoczky G, Csordas G, Yi M: Old players in a new role: Mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria. Cell Calcium 32: 363–377, 2002
Vance JE: Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265: 7248–7256, 1990
Cui Z, Vance JE, Chen MH, Voelker DR, Vance DE: Cloning and expression of a novel phosphatidylethanolamine N-methyltransferase: A specific biochemical and cytological marker for a unique membrane fraction in rat liver. J Biol Chem 268: 6655–16663, 1993
Vidugiriene J, Sharma DK, Smith TK, Baumann NA, Menon AK: Segregation of glycosylphosphatidylinositol biosynthetic reactions in A subcompartment of the endoplasmic reticulum. J Biol Chem 274: 15203–15212, 1999
Voelker DR: New perspectives on the regulation of intermembrane glycerophospholipid traffic. J Lipid Res 44: 441–449, 2003
Kennedy SG, Kandel ES, Cross TK, Hay N: Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome C from mitochondria. Mol Cell Biol 19: 5800–5810, 1999
Colavecchia M, Christie LN, Kanwar YS, Hood DA: Functional consequences of thyroid hormone-induced changes in the mitochondrial protein import pathway. Am J Physiol Endocrinol Metab 284: E29—E35, 2003
Schneider JJ, Hood DA: Effect of thyroid hormone on mtHsp70 expression, mitochondrial import and processing in cardiac muscle. J Endocrinol 165: 9–17, 2000
Chandel NS, Schumacker PT: Cellular oxygen sensing by mitochondria: Old questions, new insight. J Appl Physiol 88: 1880–1889, 2000
Duranteau J, Chandel NS, Kulisz A, Shao Z, Schumacker PT: Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 273: 11619–11624, 1998
Poderoso JJ, Peralta JG, Lisdero CL, Carreras MC, Radisic M, Schopfer F, Cadenas E, Boveris A: Nitric oxide regulates oxygen uptake and hydrogen peroxide release by isolated beating rat heart. Am J Physiol 274: C112–C119, 1998
Brookes P, Darley-Usmar VM: Hypothesis: The mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: An alternative function for cytochrome C oxidase. Free Radic Biol Med 32: 370–374, 2002
Brown GC: Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome C oxidase. Biochim Biophys Acta 1504: 46–57, 2001
Barbe P, Larrouy D, Boulanger C, Chevillotte E, Viguerie N, Thalamas C, Trastoy MO, Roques M, Vidal H, Langin D: Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB J 15: 13–15, 2001
Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB: Fatty acid-induced apoptosis in neonatal cardiomyocytes: Redox signaling. Antioxid Redox Signal 3: 71–79, 2001
Herzig RP, Scacco S, Scarpulla RC: Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome C. J Biol Chem 275: 13134–13141, 2000
Dorward A, Sweet S, Moorehead R, Singh G: Mitochondrial contributions to cancer cell physiology: Redox balance, cell cycle, and drug resistance. J Bioenerg Biomembr 29: 385–392, 1997
Scheller K, Seibel P, Sekeris CE: Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol 222: 1–61, 2003
Enriquez JA, Fernandez-Silva P, Garrido-Perez N, Lopez-Perez MJ, Perez-Martos A, Montoya J: Direct regulation of mitochondrial RNA synthesis by thyroid hormone. Mol Cell Biol 19: 657–670, 1999
Sterling K: Thyroid hormone action: Identification of the mitochondrial thyroid hormone receptor as adenine nucleotide translocase. Thyroid 1: 167–171, 1991
Lecour S, Smith RM, Woodward B, Opie LH, Rochette L, Sack MN: Identification of a novel role for sphingolipid signaling in TNFalpha and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol 34: 509–518, 2002
Martinou JC, Green DR: Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2: 63–67, 2001
Carrasco AJ, Dzeja PP, Alekseev AE, Pucar D, Zingman LV, Abraham MR, Hodgson D, Bienengraeber M, Puceat M, Janssen E, Wieringa B, Terzic A: Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci USA 98: 7623–7628, 2001
Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G: Signal transduction of ischemic preconditioning. Cardiovasc Res 52: 181—198, 2001
Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio R, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive 16 K+ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072–1082, 1997
Halestrap AP: Regulation of mitochondrial metabolism through changes in matrix volume. Biochem Soc Trans 22: 522–529, 1994
Mattson MP, Liu D: Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochem Biophys Res Commun 304: 539–549, 2003
Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O'Rourke B: Cytoprotective role of Ca2+ activated K+ channels in the cardiac inner mitochondrial membrane. Science 298: 1029–1033, 2002
Boehm EA, Jones BE, Radda GK, Veech RL, Clarke K: Increased uncoupling proteins and decreased efficiency in palmitate-perfused hyperthyroid rat heart. Am J Physiol Heart Circ Physiol 280: H977—H983, 2001
Zhou M, Lin BZ, Coughlin S, Vallega G, Pilch PF: UCP-3 expression in skeletal muscle: Effects of exercise, hypoxia, and AMP-activated protein kinase. Am J Physiol Endocrinol Metab 279: E622–E629, 2000
Moreno M, Lombardi A, De Lange P, Silvestri E, Ragni M, Lanni A, Goglia F: Fasting, lipid metabolism, and triiodothyronine in rat gastrocnemius muscle: Interrelated roles of uncoupling protein 3, mitochondrial thioesterase, and coenzyme Q. FASEB J 17: 1112–1114, 2003
Schafer M, Schafer C, Ewald N, Piper HM, Noll T: Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res 92: 1010–1015, 2003
Hoth M, Fanger CM, Lewis RS: Mitochondrial regulation of storeoperated calcium signaling in T lymphocytes. J Cell Biol 137: 633—648, 1997
Glitsch MD, Bakowski D, Parekh AB: Store-operated Ca(2+) entry depends on mitochondrial Ca(2+) uptake. EMBO J 21: 6744–6754, 2002
Maechler P: Mitochondria as the conductor of metabolic signals for insulin exocytosis in pancreatic beta-cells. Cell Mol Life Sci 59: 1803–1818, 2002
McDaniel ML, Marshall CA, Pappan KL, Kwon G: Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells Diabetes 51: 2877–2885, 2002
Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML: Metabolic regulation by leucine of translation initiation through the mTORsignaling pathway by pancreatic beta-cells. Diabetes 50: 353–360, 2001
Desai BN, Myers BR, Schreiber SL: FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA 99: 4319–4324, 2002
Tong WH, Rouault T: Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. EMBO J 19: 5692–5700, 2000
Lill R, Diekert K, Kaut A, Lange H, PelzerW, Prohl C, Kispal G: The essential role of mitochondria in the biogenesis of cellular iron-sulfur proteins. Biol Chem 380: 1157–1166, 1999
Drapier JC: Interplay between NO and [Fe-S] clusters: Relevance to biological systems. Methods 11: 319–329, 1997
Biswas G, Adebanjo OA, Freedman BD, Anandatheerthavarada HK, Vijayasarathy C, Zaidi M, Kotlikoff M, Avadhani NG: Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: A novel mode of inter-organelle crosstalk. EMBO J 18: 522–533, 1999
Amuthan G, Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG: Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21: 7839–7849, 2002
Li K, Neufer PD, Williams RS: Nuclear responses to depletion of mitochondrial DNA in human cells. AmJ Physiol 269: C1265–C1270, 1995
Dey R, Moraes CT: Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-x(L) in osteosarcoma cells. J Biol Chem 275: 7087–7094, 2000
Arnould T, Vankoningsloo S, Renard P, Houbion A, Ninane N, Demazy C, Remacle J, Raes M: CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation. EMBO J 21: 53–63, 2002
Bae JS, Jang MK, Hong S, An WG, Choi YH, Kim HD, Cheong J: Phosphorylation of NF-kappa B by calmodulin-dependent kinase IV activates anti-apoptotic gene expression. Biochem Biophys Res Commun 305: 1094–1098, 2003
Szewczyk A, Wojtczak L: Mitochondria as a pharmacological target. Pharmacol Rev 54: 101–127, 2002
Akao M, O'Rourke B, Kusuoka H, Teshima Y, Jones SP, Marbán E: Differential actions of cardioprotective agents on the mitochondrial death pathway. Circ Res 92: 195–202, 2003
Marin-Garcia J, Goldenthal MJ: Mitochondria play a critical role in cardioprotection. J Card Fail 10: 55–66, 2004
Marin-Garcia J, Goldenthal MJ, MoeGW: Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure. J Card Fail 8: 326–332, 2002
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Goldenthal, M.J., Marín-García, J. Mitochondrial signaling pathways: A receiver/integrator organelle. Mol Cell Biochem 262, 1–16 (2004). https://doi.org/10.1023/B:MCBI.0000038228.85494.3b
Issue Date:
DOI: https://doi.org/10.1023/B:MCBI.0000038228.85494.3b