1. Shin, Y., and Brangwynne, C.P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).
2. Boeynaems, S., Alberti, S., Fawzi, N.L., Mittag, T., Polymenidou, M., Rousseau, F., Schymkowitz, J., Shorter, J., Wolozin, B., Van Den Bosch, L., et al. Protein Phase Separation: A New Phase in Cell Biology. Trends Cell Biol. 28, 420–435 (2018).
3. Alberti, S., Gladfelter, A., and Mittag, T. Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates. Cell 176, 419–434 (2019).
4. Sabari, B.R., Dall'Agnese, A., Boija, A., Klein, I.A., Coffey, E.L., Shrinivas, K., Abraham, B.J., Hannett, N.M., Zamudio, A.V., Manteiga, J.C., et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).
5. Case, L.B., Zhang, X., Ditlev, J.A., and Rosen, M.K. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science 363, 1093–1097 (2019).
6. Huang, W.Y.C., Alvarez, S., Kondo, Y., Lee, Y.K., Chung, J.K., Lam, H.Y.M., Biswas, K.H., Kuriyan, J., and Groves, J.T. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science 363, 1098–1103 (2019).
7. Du, M.J., and Chen, Z.J.J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361, 704–709 (2018).
8. Woodruff, J.B., Gomes, B.F., Widlund, P.O., Mahamid, J., Honigmann, A., and Hyman, A.A. The centrosome is a selective condensate that nucleates microtubules by concentrating tubulin. Cell 169, 1066–1077 (2017).
9. Rai, A.K., Chen, J.X., Selbach, M., and Pelkmans, L. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature 559, 211–216 (2018).
10. Welch, G.R. On the role of organized multienzyme systems in cellular metabolism: a general synthesis. In Prog. Biophys. Mol. Biol. (London, UK: Elsevier), pp. 103–191 (1977).
11. Srere, P.A. COMPLEXES OF SEQUENTIAL METABOLIC ENZYMES. Annu. Rev. Biochem. 56, 89–124 (1987).
12. Jin, M.Y., Fuller, G.G., Han, T., Yao, Y., Alessi, A.F., Freeberg, M.A., Roach, N.P., Moresco, J.J., Karnovsky, A., Baba, M., et al. Glycolytic Enzymes Coalesce in G Bodies under Hypoxic Stress. Cell Rep. 20, 895–908 (2017).
13. Lee, H., DeLoache, W.C., and Dueber, J.E. Spatial organization of enzymes for metabolic engineering. Metab. Eng. 14, 242–251 (2012).
14. Kohnhorst, C.L., Kyoung, M., Jeon, M., Schmitt, D.L., Kennedy, E.L., Ramirez, J., Bracey, S.M., Luu, B.T., Russell, S.J., and An, S. Identification of a multienzyme complex for glucose metabolism in living cells. J. Biol. Chem. 292, 9191–9203 (2017).
15. Schmitt, D.L., and An, S. Spatial Organization of Metabolic Enzyme Complexes in Cells. Biochemistry 56, 3184–3196 (2017).
16. An, S.G., Kumar, R., Sheets, E.D., and Benkovic, S.J. Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320, 103–106 (2008).
17. Macfarlane, M.G. Structure of cardiolipin. Nature 182, 946 (1958).
18. Ikon, N., and Ryan, R.O. Cardiolipin and mitochondrial cristae organization. Biochim. Biophys. Acta (BBA)-Biomembranes 1859, 1156–1163 (2017).
19. Paradies, G., Paradies, V., De Benedictis, V., Ruggiero, F.M., and Petrosillo, G. Functional role of cardiolipin in mitochondrial bioenergetics. Biochim. Biophys. Acta (BBA)-Bioenergetics 1837, 408–417 (2014).
20. Ren, M.D., Phoon, C.K.L., and Schlame, M. Metabolism and function of mitochondrial cardiolipin. Prog. Lipid Res. 55, 1–16 (2014).
21. Potting, C., Tatsuta, T., König, T., Haag, M., Wai, T., Aaltonen, M.J., and Langer, T. TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab. 18, 287–295 (2013).
22. Ye, C., Shen, Z., and Greenberg, M.L. Cardiolipin remodeling: a regulatory hub for modulating cardiolipin metabolism and function. J. Bioenerg. Biomembr. 48, 113–123 (2016).
23. Paradies, G., Paradies, V., Ruggiero, F.M., and Petrosillo, G. Role of cardiolipin in mitochondrial function and dynamics in health and disease: Molecular and pharmacological aspects. Cells 8, 728 (2019).
24. Saric, A., Andreau, K., Armand, A.S., Moller, I.M., and Petit, P.X. Barth syndrome: from mitochondrial dysfunctions associated with aberrant production of reactive oxygen species to pluripotent stem cell studies. Front Genet. 6: 359 (2016)
25. Acehan, D., Xu, Y., Stokes, D.L. and Schlame, M. Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography. Lab Invest. 87, 40-48 (2006).
26. Dudek, J., Cheng, I.F., Balleininger, M., Vaz, F.M., Streckfuss-Bomeke, K., Hubscher, D., Vukotic, M., Wanders, R.J., Rehling, P. and Guan, K. Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. Stem Cell Res. 11, 806-819 (2013).
27. Miyamoto, Y., Kitamura, N., Nakamura, Y., Futamura, M., Miyamoto, T., Yoshida, M., Ono, M., Ichinose, S., and Arakawa, H. Possible Existence of Lysosome-Like Organella within Mitochondria and Its Role in Mitochondrial Quality Control. PLoS One 6, e16054 (2011).
28. Kamino, H., Nakamura, Y., Tsuneki, M., Sano, H., Miyamoto, Y., Kitamura, N., Futamura, M., Kanai, Y., Taniguchi, H., Shida, D., et al. Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer. Oncogenesis 5, e181 (2016).
29. Okuyama, K., Kitajima, Y., Egawa, N., Kitagawa, H., Ito, K., Aishima, S., Yanagihara, K., Tanaka, T., and Noshiro, H. Mieap-induced accumulation of lysosomes within mitochondria (MALM) regulates gastric cancer cell invasion under hypoxia by suppressing reactive oxygen species accumulation. Sci. Rep. 9, 2822 (2019).
30. Tsuneki, M., Nakamura, Y., Kinjo, T., Nakanishi, R., and Arakawa, H. Mieap suppresses murine intestinal tumor via its mitochondrial quality control. Sci. Rep. 5, 12472 (2015).
31. Mussazhanova, Z., Shimamura, M., Kurashige, T., Ito, M., Nakashima, M., and Nagayama, Y. Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors. Cancer Sci. 111, 2814–2823 (2020).
32. Gaowa, S., Futamura, M., Tsuneki, M., Kamino, H., Tajima, J.Y., Mori, R., Arakawa, H., and Yoshida, K. Possible role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in human breast cancer. Cancer Sci. 109, 3910–3920 (2018).
33. Kitamura, N., Nakamura, Y., Miyamoto, Y., Miyamoto, T., Kabu, K., Yoshida, M., Futamura, M., Ichinose, S., and Arakawa, H. Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria. PLoS One 6, e16060 (2011).
34. Kriventseva, E.V., Kuznetsov, D., Tegenfeldt, F., Manni, M., Dias, R., Simao, F.A., and Zdobnov, E.M. OrthoDB v10: sampling the diversity of animal, plant, fungal, protist, bacterial and viral genomes for evolutionary and functional annotations of orthologs. Nucleic Acids Res. 47, D807–D811 (2019).
35. Huang, Y.J., Acton, T.B., and Montelione, G.T. DisMeta: a meta server for construct design and optimization. Methods Mol. Biol. 1091, 3–16 (2014).
36. Uversky, V.N., Radivojac, P., Iakoucheva, L.M., Obradovic, Z., and Dunker, A.K. Prediction of intrinsic disorder and its use in functional proteomics. Methods Mol. Biol. 408, 69–92 (2007).
37. Lupas, A., Van Dyke, M., and Stock, J. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).
38. Holehouse, A.S., Das, R.K., Ahad, J.N., Richardson, M.O., and Pappu, R.V. CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins. Biophys. J. 112, 16–21 (2017).
39. Kyte, J., and Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982).
40. Kaewsuya, P., Danielson, N.D., and Ekhterae, D. Fluorescent determination of cardiolipin using 10-N-nonyl acridine orange. Anal. Bioanal. Chem. 387, 2775–2782 (2007).
41. Sathappa, M. and Alder, N.N. The ionization properties of cardiolipin and its variants in model bilayers. Biochim. Biophys. Acta. 1858, 1362-1372 (2016).
42. Belazi, D., Sole-Domenech, S., Johansson, B., Schalling, M., and Sjovall, P. Chemical analysis of osmium tetroxide staining in adipose tissue using imaging ToF-SIMS. Histochem. Cell Biol. 132, 105–115 (2009).
43. Planas-Iglesias, J., Dwarakanath, H., Mohammadyani, D., Yanamala, N., Kagan, V.E., and Klein-Seetharaman, J. Cardiolipin Interactions with Proteins. Biophys. J. 109, 1282–1294 (2015).
44. Miyamoto, T., Kitamura, N., Ono, M., Nakamura, Y., Yoshida, M., Kamino, H., Murai, R., Yamada, T., and Arakawa, H. Identification of 14-3-3γ as a Mieap-interacting protein and its role in mitochondrial quality control. Sci. Rep. 2, 379 (2012).
45. Munnik, T., and Wierzchowiecka, M. Lipid-binding analysis using a fat blot assay. Methods Mol. Biol. 1009, 253–259 (2013).
46. Bota, D.A., and Davies, K.J. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat. Cell Biol. 4, 674–680 (2002).
47. Choi, S.Y., Huang, P., Jenkins, G.M., Chan, D.C., Schiller, J., and Frohman, M.A. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat. Cell Biol. 8, 1255–1262 (2006).
48. Lee, J.H., Park, A., Oh, K.-J., Lee, S.C., Kim, W.K., and Bae, K.-H. The role of adipose tissue mitochondria: Regulation of mitochondrial function for the treatment of metabolic diseases. Int. J. Mol. Sci. 20, 4924 (2019).
49. Sidossis, L. and Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 125, 478–486 (2015).
50. Fenzl, A. and Kiefer, F.W. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig. 19, 25–37 (2014).
51. Crichton, P.G., Lee, Y., and Kunji, E.R. The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism. Biochimie. 134, 35–50 (2017).
52. Castellana, M., Wilson, M.Z., Xu, Y.F., Joshi, P., Cristea, I.M., Rabinowitz, J.D., Gitai, Z., and Wingreen, N.S. Enzyme clustering accelerates processing of intermediates through metabolic channeling. Nat. Biotechnol. 32, 1011–1018 (2014).
53. Prouteau, M., and Loewith, R. Regulation of Cellular Metabolism through Phase Separation of Enzymes. Biomolecules 8, 160 (2018).
54. Strulson, C.A., Molden, R.C., Keating, C.D., and Bevilacqua, P.C. RNA catalysis through compartmentalization. Nat. Chem. 4, 941–946 (2012).
55. Bracha, D., Walls, M.T., and Brangwynne, C.P. Probing and engineering liquid-phase organelles. Nat. Biotechnol. 37, 1435–1445 (2019).
56. Zhao, E.M., Suek, N., Wilson, M.Z., Dine, E., Pannucci, N.L., Gitai, Z., Avalos, J.L., and Toettcher, J.E. Light-based control of metabolic flux through assembly of synthetic organelles. Nat. Chem. Biol. 15, 589–597 (2019).
57. Hinzpeter, F., Gerland, U., and Tostevin, F. Optimal Compartmentalization Strategies for Metabolic Microcompartments. Biophys. J. 112, 767–779 (2017).
58. Kojima, T., and Takayama, S. Membraneless Compartmentalization Facilitates Enzymatic Cascade Reactions and Reduces Substrate Inhibition. ACS Appl. Mater. Interfaces 10, 32782–32791 (2018).
59. Dan, X., Babbar, M., Moore, A., Wechter, N., Tian, J., Mohanty, J.G., Croteau, D.L., and Bohr, V.A. DNA damage invokes mitophagy through a pathway involving Spata18. Nucleic Acids Res. 48, 6611–6623 (2020).
60. Tatsuta, T. and Langer, T. Quality control of mitochondria: protection against neurodegeneration and aging. EMBO J. 27, 306-314 (2008).
61. Oshima, H., Matsunaga, A., Fujimura, T., Tsukamoto, T., Taketo, M.M., and Oshima, M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E-2 pathway. Gastroenterology 131, 1086–1095 (2006).
62. Serricchio, M., Vissa, A., Kim, P.K., Yip, C.M., and McQuibban, G.A. Cardiolipin synthesizing enzymes form a complex that interacts with cardiolipin-dependent membrane organizing proteins. Biochim. Biophys. Acta-Mol. Cell Biol. Lipids 1863, 447–457 (2018).
63. Goldstein, J.C., Waterhouse, N.J., Juin, P., Evan, G.I., and Green, D.R. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156–162 (2000).
64. Nakamura, Y., Kitamura, N., Shinogi, D., Yoshida, M., Goda, O., Murai, R., Kamino, H., and Arakawa, H. BNIP3 and NIX mediate Mieap-induced accumulation of lysosomal proteins within mitochondria. PLoS One 7, e30767 (2012).
65. Oda, K., Arakawa, H., Tanaka, T., Matsuda, K., Tanikawa, C., Mori, T., Nishimori, H., Tamai, K., Tokino, T., Nakamura, Y., et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000).
66. Wilkins, M.R., Gasteiger, E., Bairoch, A., Sanchez, J.C., Williams, K.L., Appel, R.D., and Hochstrasser, D.F. Protein identification and analysis tools in the ExPASy server. Methods Mol. Biol. 112, 531–552 (1999).
67. Shindou, H., Koso, H., Sasaki, J., Nakanishi, H., Sagara, H., Nakagawa, K.M., Takahashi, Y., Hishikawa, D., Iizuka-Hishikawa, Y., Tokumasu, F., et al. Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells. J. Biol. Chem. 292, 12054–12064 (2017).
68. Yamamoto, T., Endo, J., Kataoka, M., Matsuhashi, T., Katsumata, Y., Shirakawa, K., Yoshida, N., Isobe, S., Moriyama, H., Goto, S., et al. Decrease in membrane phospholipids unsaturation correlates with myocardial diastolic dysfunction. PLoS One 13, e0208396 (2018).
69. Bligh, E.G., and Dyer, W.J. A rapid method of total lipid extraction and purification. Can. J. Biochem. 37, 911–917 (1959).
70. Schneider, C.A., Rasband, W.S., and Eliceiri, K.W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).