Phosphatidylglycerol-containing ER-transport vesicles built and restore outer mitochondrial membrane and deliver nuclear DNA translation products to generate cardiolipin in the inner mitochondrial membrane


Phosphatidylglycerol (PG) an important membrane phospholipid required for the synthesis of diphos-phatidylglycerol (DPG) commonly known as cardiolipin (CL) was identified in the fraction of endo-plasmic reticulum (ER)-derived transport vesicles which had no affinity for Golgi. The vesicles were produced in the presence of Brefeldin A (BFA), the agent known to inhibit ER-Golgi transport, and found to display affinity to mitochondria. The analysis revealed that their cargo was not containing proteins that are transported to Golgi, and that their membrane was free of phosphatidylinositol (PI) and ceramides (Cer). The incubation of PG-containing transport vesicles with mitochondria afforded incorporation of their membrane into the Outer Mito-chondrial Membrane (OMM) and formation of lyso-phosphatidylglycerol (LPG). In turn, upon further incubation with fresh transport active cytosol, the mitochondrial LPG was converted to PG. The results of analysis of the OMM, Inner Mitochondrial Mem-brane (IMM) and Inner Mitochondrial Space Components (IMSC) strongly suggest that PG-containing transport vesicles deliver nuclear DNA translation products to the IMSC and thus facilitate CL synthesis in the IMM. In summary, our studies provide evidence that ER-generated PG-enriched transport vesicles represent the general pathway for restitution of mitochondrial membranes and the delivery of nuclear DNA translation products that generate CL, and thus sustain the mitochondrial matrix CL-dependent metabolic reactions.

Share and Cite:

Slomiany, A. and Slomiany, B. (2012) Phosphatidylglycerol-containing ER-transport vesicles built and restore outer mitochondrial membrane and deliver nuclear DNA translation products to generate cardiolipin in the inner mitochondrial membrane. Advances in Biological Chemistry, 2, 132-145. doi: 10.4236/abc.2012.22016.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Croze, E.M. and Morre, D.J. (1984) Isolation of plasma membrane, Golgi apparatus, and endoplasmic reticulum from single homogenates of mouse liver. Journal of Cellular Physiology, 119, 46-57. doi:10.1002/jcp.1041190109
[2] Slomiany, A., Sano, S., Grabska, M., Yamaki, K. and Slomiany, B.L. (2004) Gastric mucosal cell homeostatic physiome. Critical role of ER-initiated membrane restitution in the fidelity of cell function renewal. Journal of Physiology and Pharmacology, 55, 837-860.
[3] Slomiany, A. and Slomiany, B.L. (2010) Cell membranes composition is defined in ER and their restitution proceeds by en bloc fusion of ER generated transport vesicles. Health, 2, 1444-1454. doi:10.4236/health.2010.212214
[4] Slomiany, A. and Slomiany, B.L. (2011) Transformations of phosphatidylinositol phosphates in the outer and inner nuclear membrane are linked to synthesis and restitution of cellular membranes. Health, 3, 187-199, doi:10.4236/health.2011.34035
[5] Rothman, J.E. (1994) Mechanisms of intracellular protein transport. Nature, 372, 55-63. doi:10.1038/372055a0
[6] Lemmon, M.A. (2008) Membrane recognition by phospholipids binding proteins. National Review of the Molecular Cell Biology, 9, 99-111. doi:10.1038/nrm2328
[7] Slomiany, A., Grabska, M. and Slomiany, B.L. (2006) Homeostatic restitution of cell membranes. Nuclear membrane lipid biogenesis and transport of protein from cytosol to intranuclear spaces. International Journal of Biological Sciences, 2, 216-226. doi:10.7150/ijbs.2.216
[8] Slomiany, A. and Slomiany, B.L. (2003) Lipidomic processes in homeostatic and LPS-modified cell renewal cycle. Role of phosphatidylinositol 3-kinase pathway in biomembrane synthesis and restitution of apical epithelial membrane. Journal Physiology and Pharmacology, 54, 533-551.
[9] Slomiany, A., Grabska, M., Piotrowski, E. and Slomiany, B.L. (1994) Intracellular processes associated with vesicular transport from endoplasmic reticulum to Golgi and exocytosis. Archives of Biochemistry and Biophysics, 310, 247-255. doi:10.1006/abbi.1994.1164
[10] Slomiany, A., Grzelinska, E., Grabska, M. and Slomiany, B.L. (1992) Intracelular processes associated with glycoprotein transport and processing. Archives of Biochemistry and Biophysics, 298, 167-175. doi:10.1016/0003-9861(92)90108-9
[11] Slomiany, A., Nowak, P., Piotrowski, E. and Slomiany, B.L. (1998) Effect of ethanol on intracellular vesicular transport from Golgi to the apical membrane. Role of phosphatidylinositol 3-kinase and phospholipase A2 in Golgi transport vesicles association and fusion with the apical membrane. Alcohol, Clinical and Experimental Research, 22, 167-175. doi:10.1111/j.1530-0277.1998.tb03634.x
[12] Neupert, H. and Herrmann, J.M. (2007) Translocation of proteins into mitochondria. Annual Review of Biochemistry, 76, 723-749. doi:10.1146/annurev.biochem.76.052705.163409
[13] Becker, T., Gebert, M., Pfanner, N. and van der Lannn, M. (2009) Biogenesis of mitochondrial membrane proteins. Current Opinions in Cell Biology, 21, 484-493. doi:10.1016/
[14] Osman, C., Voelker, D.R. and Langer, T. (2011) Making heads or tails of phospholipids in mitochondria. Journal of Cell Biology, 192, 7-16.
[15] Claypool, S.M., Octay, Y., Boontheung, P., Loo, J.A. and Koehler, C.M. (2008) Cardiolipin defines the interactome of the major carrier protein of mitochondrial inner membrane. Journal of Cell Biology, 182, 937-950. doi:10.1083/jcb.200801152
[16] Parsons, D.F., Willims, G.R. and Chance, B. (1966) Cha- racteristics of isolated and purified preparations of the outer and inner membranes of mitochondria. Annals of the New York Academy of Sciences, 137, 643-666. doi:10.1111/j.1749-6632.1966.tb50188.x
[17] Cobon, G.S., Crowfoot, D. and Linnane, W. (1974) Biogenesis of mitochondria. Phospholipid synthesis in vitro by yeast mitochondrial and microsomal fractions. Biochemistry Journal, 144, 265-275.
[18] Gohil, V.M. and Greenberg, M.L. (2009) Mitochondrial membrane biogenesis: Phospholipids and proteins go hand in hand. Journal of Cell Biology, 184, 469-472.
[19] Klausner, R.D., Donaldson, J.G. and Lippincott-Schwartz, J. (1992) Brefeldin A: Insights into the control of membrane traffic and organelle structure. Journal of Cell Biology, 116, 1071-1080. doi:10.1083/jcb.116.5.1071
[20] Slomiany, A., Grabska, M. and Slomiany, B.A., et al. (1993) Intracellular transport, organelle biogenesis and establishment of Golgi identity: Impact of Brefeldin A on the activity of lipid synthesizing enzymes. International Journal of Biochemistry, 25, 891-901. doi:10.1016/0020-711X(93)90245-A
[21] Idone, V., Tam, C. and Andrews, N.W. (2008) Two-way traffic on the road to plasma membrane repair. Trends in Cellular Biology, 18, 552-559. doi:10.1016/j.tcb.2008.09.001
[22] Slomiany, A., Grzelinska, E., Yamaki, K. and Slomiany, B.L. (1992) Function of intracellular phospholipase A2 in vectorial transport of apoproteins from ER to Golgi. International Journal of Biochemistry, 24, 1397-1406.
[23] Saini-chohan, H.K., Holmes, M.G. and Chicco, A.J., et al. (2009) Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure. Journal of Lipid Research, 50, 1600-1608. doi:10.1194/jlr.M800561-JLR200
[24] Helmy, F.M. (2006) Cardiolipin, its preferential deacylation in mammalian myocardia. Mini review and chromatographic-computational analysis. Acta Chromatographica, 17, 9-19.
[25] Cao, J., Liu, Y., Lockwood, J., Burn, P. and Shi, Y. (2004) A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl- CoA: Lysocardiolipin acyltransferase (ALCAT1) in mouse. The Journal of Biological Chemistry, 279, 31727-31734. doi:10.1074/jbc.M402930200
[26] Beck, R., Prinz, S. and Distellkoter-Bechart, P., et al. (2011) Coatomer and dimeric ADP ribosylation factor 1 promote distinct steps in membrane scission. Journal of Cell Biology, 194, 765-777.
[27] Sarrl, E., Sicart, A., Lazaro-Dieguez, F. and Egea, G. (2011) Phospholipid synthesis participates in the regulation of diacylglycerol required for membrane trafficking at Golgi complex. The Journal of Biological Chemistry, 286, 28632-28643. doi:10.1074/jbc.M111.267534
[28] Ma, C., Agrawal, G. and Subramani, S. (2011) Peroxisome assembly: Matrix and membrane protein biogenesis. Journal of Cell Biology, 193, 7-16. doi:10.1083/jcb.201010022
[29] Sudhof, T.C. and Rothman, J.E. (2009) Membrane fusion; Grappling with SNARE and SM proteins. Science, 323, 474-477. doi:10.1126/science.1161748
[30] Glick, B.S. and Nakano, A. (2009) Membrane traffic within the Golgi apparatus. Annual Review of Cell Development Biology, 25, 113-132. doi:10.1146/annurev.cellbio.24.110707.175421
[31] Chapman, E.R. (2008) How does synaptotagmin trigger neurotransmitter release? Annual Review of Biochemistry, 77, 615-641. doi:10.1146/annurev.biochem.77.062005.101135
[32] van Meer, G., Halter, D., Sprong, H., Somerharju, P. and Egmond, M.R. (2006) ABC lipid transporters: Extruders, flippases, or flopless activators? FEBS Letters, 580, 1171- 1177. doi:10.1016/j.febslet.2005.12.019
[33] Kawano, M., Kumagai, K., Nishijima, M. and Handa, K. (2006) Efficient trafficking of ceramide from endoplasmic reticulum to the Golgi apparatus requires VAMP- associated protein interacting FFAT motif of CERT. Journal of Biological Chemistry, 281, 30279-30288. doi:10.1074/jbc.M605032200
[34] Mellman, I. and Nelson, W.J. (2009) Coordinated protein sorting, targeting and distribution in polarized cells. National Review of the Molecular Cell Biology, 9, 833-845. doi:10.1038/nrm2525
[35] Slomiany, A., Grzelinska, E. and Kasinathan, C., et al. (1992) Biogenesis of endoplasmic reticulum transport vesicles transferring gastric apomucin from ER to Golgi. Experimental Cell Research, 201, 1669-1682. doi:10.1016/0014-4827(92)90280-L
[36] Simmen, T., Lynes, E.M., Gesson, K. and Thomas, G. (2010) Oxidative protein folding in the endoplasmic reticulum: Tight links to the mitochondria-associated membrane (MAM). Biochimica et Biophysica Acta (BBA): Biomembranes, 1798, 1465-1473. doi:10.1016/j.bbamem.2010.04.009
[37] Berridge, M.J. (2002) The endoplasmic reticulum; a multifunctional signaling organelle. Cell Calcium, 32, 235- 249. doi:10.1016/S0143416002001823
[38] Nie, J., Hao, X. and Chen, D., et al. (2010) A novel function of the human CLS1 in phosphatidylglycerol synthesis and remodeling. Biochimica et Biophysica Acta (BBA): Biomembranes, 1801, 438-445. doi:10.1016/j.bbalip2009.12.002
[39] Houtkooper, R.H. and Vaz, F.M. (2008) Cardiolipin the heart of mitochondrial metabolism. Cellular and Molecular Life Sciences, 65, 2493-2414. doi:10.1007/s00018-008-8030-5
[40] Zachman, D.K.K., Chicco, A.J. and McCune, S.A., et al. (2010) The role of calcium-independent phospholipase A2 in cardiolipin remodeling in the spontaneously hypertensive heart failure rat heart. Journal Lipid Research, 51, 525-534. doi:10.1194/jlr.M000646
[41] Darios, F., Ruiperez, V. and Lopez, I., et al. (2010) Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Reports, 11, 528-533. doi:10.1038/embor.2010.66
[42] Chen, D., Zhang H.-Y. and Shi, Y. (2006) Identification and functional characterization of hCLs1, a human cardiolipin synthase localized in mitochondria. Biochemical Journal, 398, 169-176. doi:10.1042/BJ20060303
[43] Osman, C., Haag, M., Wieland, F.T., Brugger, B. and Langer, T. (2010) A mitochondrial phosphatase required for cardiolipin biosynthesis: The PGP phosphatase Gep4. The EMBO Journal, 29, 1976-1987. doi:10.1038/emboj.2010.98
[44] Gebert, N., Joshi, A.S. and Kutik, S., et al. (2009) Mitochondrial cardiolipin involved in outer-membrane biogenesis: Implications for Barth syndrome. Current Biology, 19, 2133-2139.
[45] Nie, J., Hao, X. and Chen, D., et al. (2010) A novel function of the human CLS1 in phosphatidylglycerol synthesis and remodeling. Biochimica et Biophysica Acta, 1801, 438-445. doi:10.1016/jbbalip.2009.12.002
[46] Yang, Y., Cao, J. and Shi, Y. (2004) Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase. The Journal Biological Chemistry, 279, 55866-55874. doi:10.1074/jbc.M406710200
[47] Kawasaki, K., Kuge, O. and Chang, S.-C., et al. (1999) Isolation of a chinese hamster ovary (CHO) cDNA encoding phosphatidylglycerolphosphate (PGP) synthase, expression of which corrects the mitochondrial abnormalities of a PGP synthase-defective mutant of CHO-K1 cells. The Journal of Biological Chemistry, 274, 1828-1834. doi:10.1074/jbc.274.3.1828
[48] Chen, D., Zhang, X.-U. and Shi, Y. (2006) Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria. Biochemical Journal, 398, 169-176. doi:10.1042/BJ20060303
[49] Giorgi, C., De Stefani, D., Bononi, A., Rizzuto, R. and Pinton, P. (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. International Journal of Biochemistry and Cell Biology, 41, 1817-1827. doi:10.1016/j.biocel.2009.04.010

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.