1932

Abstract

Mitochondria are involved in multiple cellular tasks, such as ATP synthesis, metabolism, metabolite and ion transport, regulation of apoptosis, inflammation, signaling, and inheritance of mitochondrial DNA. The majority of the correct functioning of mitochondria is based on the large electrochemical proton gradient, whose component, the inner mitochondrial membrane potential, is strictly controlled by ion transport through mitochondrial membranes. Consequently, mitochondrial function is critically dependent on ion homeostasis, the disturbance of which leads to abnormal cell functions. Therefore, the discovery of mitochondrial ion channels influencing ion permeability through the membrane has defined a new dimension of the function of ion channels in different cell types, mainly linked to the important tasks that mitochondrial ion channels perform in cell life and death. This review summarizes studies on animal mitochondrial ion channels with special focus on their biophysical properties, molecular identity, and regulation. Additionally, the potential of mitochondrial ion channels as therapeutic targets for several diseases is briefly discussed.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biophys-092622-094853
2023-05-09
2024-05-06
Loading full text...

Full text loading...

/deliver/fulltext/biophys/52/1/annurev-biophys-092622-094853.html?itemId=/content/journals/10.1146/annurev-biophys-092622-094853&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA et al. 2014. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. PNAS 111:10580–85
    [Google Scholar]
  2. 2.
    Alevriadou BR, Patel A, Noble M, Ghosh S, Gohil VM et al. 2021. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am. J. Physiol. Cell Physiol. 320:C465–82
    [Google Scholar]
  3. 3.
    Allawzi AM, Vang A, Clements RT, Jhun BS, Kue NR et al. 2018. Activation of anoctamin-1 limits pulmonary endothelial cell proliferation via p38-mitogen-activated protein kinase-dependent apoptosis. Am. J. Respir. Cell Mol. Biol. 58:658–67
    [Google Scholar]
  4. 4.
    Amodeo GF, Scorciapino MA, Messina A, De Pinto V, Ceccarelli M. 2014. Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel. PLOS ONE 9:e103879
    [Google Scholar]
  5. 5.
    Anflous K, Armstrong DD, Craigen WJ. 2001. Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J. Biol. Chem. 276:1954–60
    [Google Scholar]
  6. 6.
    Anflous-Pharayra K, Lee N, Armstrong DL, Craigen WJ. 2011. VDAC3 has differing mitochondrial functions in two types of striated muscles. Biochim. Biophys. Acta 1807:150–56
    [Google Scholar]
  7. 7.
    Antoniel M, Jones K, Antonucci S, Spolaore B, Fogolari F et al. 2018. The unique histidine in OSCP subunit of F-ATP synthase mediates inhibition of the permeability transition pore by acidic pH. EMBO Rep 19:257–68
    [Google Scholar]
  8. 8.
    Arduino DM, Wettmarshausen J, Vais H, Navas-Navarro P, Cheng Y et al. 2017. Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Mol. Cell 67:711–23.e7
    [Google Scholar]
  9. 9.
    Ashrafuzzaman M. 2022. Mitochondrial ion channels in aging and related diseases. Curr. Aging Sci. 15:97–109
    [Google Scholar]
  10. 10.
    Augustynek B, Kunz WS, Szewczyk A. 2017. Guide to the pharmacology of mitochondrial potassium channels. Handb. Exp. Pharmacol. 240:103–27
    [Google Scholar]
  11. 11.
    Bachmann M, Rossa A, Antoniazzi G, Biasutto L, Carrer A et al. 2021. Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3. Pharmacol. Res. 164:105326–37
    [Google Scholar]
  12. 12.
    Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD. 2007. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. 9:550–55
    [Google Scholar]
  13. 13.
    Bajgar R, Seetharaman S, Kowaltowski AJ, Garlid KD, Paucek P. 2001. Identification and properties of a novel intracellular (mitochondrial) ATP-sensitive potassium channel in brain. J. Biol. Chem. 276:33369–74
    [Google Scholar]
  14. 14.
    Balderas E, Torres NS, Rosa-Garrido M, Chaudhuri D, Toro L et al. 2019. MitoBKCa channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria. J. Physiol. 597:3817–32
    [Google Scholar]
  15. 15.
    Balderas E, Zhang J, Stefani E, Toro L 2015. Mitochondrial BKCa channel. Front. Physiol. 6:104–14
    [Google Scholar]
  16. 16.
    Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA et al. 2011. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–45
    [Google Scholar]
  17. 17.
    Bayrhuber M, Meins T, Habeck M, Becker S, Giller K et al. 2008. Structure of the human voltage-dependent anion channel. PNAS 105:15370–75
    [Google Scholar]
  18. 18.
    Beavis AD, Lu Y, Garlid KD. 1993. On the regulation of K+ uniport in intact mitochondria by adenine nucleotides and nucleotide analogs. J. Biol. Chem. 268:997–1004
    [Google Scholar]
  19. 19.
    Bednarczyk P, Kicinska A, Laskowski M, Kulawiak B, Kampa R et al. 2018. Evidence for a mitochondrial ATP-regulated potassium channel in human dermal fibroblasts. Biochim. Biophys. Acta Bioenerget. 1859:309–18
    [Google Scholar]
  20. 20.
    Bednarczyk P, Kowalczyk JE, Beresewicz M, Dolowy K, Szewczyk A, Zablocka B. 2010. Identification of a voltage-gated potassium channel in gerbil hippocampal mitochondria. Biochem. Biophys. Res. Commun. 397:614–20
    [Google Scholar]
  21. 21.
    Bednarczyk P, Koziel A, Jarmuszkiewicz W, Szewczyk A. 2013. Large-conductance Ca2+-activated potassium channel in mitochondria of endothelial EA.hy926 cells. Am. J. Physiol. Heart Circ. Physiol. 304:H1415–27
    [Google Scholar]
  22. 22.
    Bednarczyk P, Wieckowski MR, Broszkiewicz M, Skowronek K, Siemen D, Szewczyk A. 2013. Putative structural and functional coupling of the mitochondrial BKCa channel to the respiratory chain. PLOS ONE 8:e68125
    [Google Scholar]
  23. 23.
    Benarroch EE. 2017. Sulfonylurea receptor-associated channels: involvement in disease and therapeutic implications. Neurology 88:314–21
    [Google Scholar]
  24. 24.
    Benz R. 2021. Historical perspective of pore-forming activity studies of voltage-dependent anion channel (eukaryotic or mitochondrial porin) since its discovery in the 70th of the last century. Front. Physiol. 12:734226
    [Google Scholar]
  25. 25.
    Bernardi P, Carraro M, Lippe G. 2022. The mitochondrial permeability transition: recent progress and open questions. FEBS J 289:227051–74
    [Google Scholar]
  26. 26.
    Bernardi P, Vassanelli S, Veronese P, Colonna R, Szabo I, Zoratti M. 1992. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J. Biol. Chem. 267:2934–39
    [Google Scholar]
  27. 27.
    Blachly-Dyson E, Forte M. 2001. VDAC channels. IUBMB Life 52:113–18
    [Google Scholar]
  28. 28.
    Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M et al. 2013. Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–83
    [Google Scholar]
  29. 29.
    Boob M, Wang Y, Gruebele M. 2019. Proteins: “boil ‘em, mash ‘em, stick ‘em in a stew. .” J. Phys. Chem. B 123:8341–50
    [Google Scholar]
  30. 30.
    Brierley GP. 1969. Energy-linked alteration of mitochondrial permeability to anions. Biochem. Biophys. Res. Commun. 35:396–402
    [Google Scholar]
  31. 31.
    Busija DW, Katakam PV. 2014. Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J. Vasc. Res. 51:175–89
    [Google Scholar]
  32. 32.
    Cancherini DV, Trabuco LG, Rebouças NA, Kowaltowski AJ. 2003. ATP-sensitive K+ channels in renal mitochondria. Am. J. Physiol. Ren. Physiol. 285:F1291–96
    [Google Scholar]
  33. 33.
    Capera J, Navarro-Pérez M, Moen AS, Szabó I, Felipe A 2022. The mitochondrial routing of the Kv1.3 channel. Front. Oncol. 12:865686
    [Google Scholar]
  34. 34.
    Capera J, Pérez-Verdaguer M, Peruzzo R, Navarro-Pérez M, Martínez-Pinna J et al. 2021. A novel mitochondrial Kv1.3-caveolin axis controls cell survival and apoptosis. eLife 10:e69099
    [Google Scholar]
  35. 35.
    Carraro M, Carrer A, Urbani A, Bernardi P. 2020. Molecular nature and regulation of the mitochondrial permeability transition pore(s), drug target(s) in cardioprotection. J. Mol. Cell. Cardiol. 144:76–86
    [Google Scholar]
  36. 36.
    Carrer A, Tommasin L, Šileikytė J, Ciscato F, Filadi R et al. 2021. Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase. Nat. Commun. 12:4835–47
    [Google Scholar]
  37. 37.
    Chaudhuri D, Sancak Y, Mootha VK, Clapham DE 2013. MCU encodes the pore conducting mitochondrial calcium currents. eLife 2:e00704
    [Google Scholar]
  38. 38.
    Checchetto V, Azzolini M, Peruzzo R, Capitanio P, Leanza L. 2018. Mitochondrial potassium channels in cell death. Biochem. Biophys. Res. Commun. 500:51–58
    [Google Scholar]
  39. 39.
    Checchetto V, Leanza L, De Stefani D, Rizzuto R, Gulbins E, Szabo I. 2021. Mitochondrial K+ channels and their implications for disease mechanisms. Pharmacol. Ther. 227:107874
    [Google Scholar]
  40. 40.
    Checchetto V, Reina S, Magri A, Szabo I, De Pinto V. 2014. Recombinant human voltage dependent anion selective channel isoform 3 (hVDAC3) forms pores with a very small conductance. Cell. Physiol. Biochem. 34:842–53
    [Google Scholar]
  41. 41.
    Checchetto V, Teardo E, Carraretto L, Leanza L, Szabo I. 2016. Physiology of intracellular potassium channels: a unifying role as mediators of counterion fluxes?. Biochim. Biophys. Acta 1857:1258–66
    [Google Scholar]
  42. 42.
    Chin HS, Li MX, Tan IKL, Ninnis RL, Reljic B et al. 2018. VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nat. Commun. 9:4976
    [Google Scholar]
  43. 43.
    Choudhary OP, Paz A, Adelman JL, Colletier JP, Abramson J, Grabe M. 2014. Structure-guided simulations illuminate the mechanism of ATP transport through VDAC1. Nat. Struct. Mol. Biol. 21:626–32
    [Google Scholar]
  44. 44.
    Conti Nibali S, Di Rosa MC, Rauh O, Thiel G, Reina S, De Pinto V 2021. Cell-free electrophysiology of human VDACs incorporated into nanodiscs: an improved method. Biophys. Rep. 1:100002
    [Google Scholar]
  45. 45.
    Correia SC, Cardoso S, Santos RX, Carvalho C, Santos MS et al. 2011. New insights into the mechanisms of mitochondrial preconditioning-triggered neuroprotection. Curr. Pharm. Des. 17:3381–9
    [Google Scholar]
  46. 46.
    Costa AD, Krieger MA. 2009. Evidence for an ATP-sensitive K+ channel in mitoplasts isolated from Trypanosoma cruzi and Crithidia fasciculata. Int. J. Parasitol. 39:955–61
    [Google Scholar]
  47. 47.
    Dahlem YA, Horn TF, Buntinas L, Gonoi T, Wolf G, Siemen D. 2004. The human mitochondrial KATP channel is modulated by calcium and nitric oxide: a patch-clamp approach. Biochim. Biophys. Acta 1656:46–56
    [Google Scholar]
  48. 48.
    De Marchi U, Basso E, Szabò I, Zoratti M. 2006. Electrophysiological characterization of the Cyclophilin D-deleted mitochondrial permeability transition pore. Mol. Membr. Biol. 23:521–30
    [Google Scholar]
  49. 49.
    De Marchi U, Checchetto V, Zanetti M, Teardo E, Soccio M et al. 2010. ATP-sensitive cation-channel in wheat (Triticum durum Desf.): identification and characterization of a plant mitochondrial channel by patch-clamp. Cell. Physiol. Biochem. 26:975–82
    [Google Scholar]
  50. 50.
    De Marchi U, Sassi N, Fioretti B, Catacuzzeno L, Cereghetti GM et al. 2009. Intermediate conductance Ca2+-activated potassium channel (KCa3.1) in the inner mitochondrial membrane of human colon cancer cells. Cell Calcium 45:509–16
    [Google Scholar]
  51. 51.
    De Marchi U, Szabò I, Cereghetti GM, Hoxha P, Craigen WJ, Zoratti M. 2008. A maxi-chloride channel in the inner membrane of mammalian mitochondria. Biochim. Biophys. Acta 1777:1438–48
    [Google Scholar]
  52. 52.
    De Mario A, Tosatto A, Hill JM, Kriston-Vizi J, Ketteler R et al. 2021. Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter. Cell Rep 35:109275
    [Google Scholar]
  53. 53.
    De Pinto V. 2021. Renaissance of VDAC: new insights on a protein family at the interface between mitochondria and cytosol. Biomolecules 11:107
    [Google Scholar]
  54. 54.
    De Pinto V, Reina S, Gupta A, Messina A, Mahalakshmi R 2016. Role of cysteines in mammalian VDAC isoforms' function. Biochim. Biophys. Acta 1857:1219–27
    [Google Scholar]
  55. 55.
    De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. 2011. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–40
    [Google Scholar]
  56. 56.
    De Stefani D, Rizzuto R, Pozzan T. 2016. Enjoy the trip: calcium in mitochondria back and forth. Annu. Rev. Biochem. 85:161–92
    [Google Scholar]
  57. 57.
    Debska G, Kicinska A, Skalska J, Szewczyk A, May R et al. 2002. Opening of potassium channels modulates mitochondrial function in rat skeletal muscle. Biochim. Biophys. Acta 1556:97–105
    [Google Scholar]
  58. 58.
    Derksen M, Vorwerk C, Siemen D. 2016. Calpeptin, not calpain, directly inhibits an ion channel of the inner mitochondrial membrane. Protoplasma 253:835–43
    [Google Scholar]
  59. 59.
    Di Marco G, Vallese F, Jourde B, Bergsdorf C, Sturlese M et al. 2020. A high-throughput screening identifies MICU1 targeting compounds. Cell Rep 30:2321–31.e6
    [Google Scholar]
  60. 60.
    Dong Z, Shanmughapriya S, Tomar D, Siddiqui N, Lynch S et al. 2017. Mitochondrial Ca2+ uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity. Mol. Cell 65:1014–28.e7
    [Google Scholar]
  61. 61.
    Douglas RM, Lai JC, Bian S, Cummins L, Moczydlowski E, Haddad GG. 2006. The calcium-sensitive large-conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain. Neuroscience 139:1249–61
    [Google Scholar]
  62. 62.
    Eddy MT, Yu TY, Wagner G, Griffin RG. 2019. Structural characterization of the human membrane protein VDAC2 in lipid bilayers by MAS NMR. J. Biomol. NMR 73:451–60
    [Google Scholar]
  63. 63.
    Fan C, Fan M, Orlando BJ, Fastman NM, Zhang J et al. 2018. X-ray and cryo-EM structures of the mitochondrial calcium uniporter. Nature 559:575–79
    [Google Scholar]
  64. 64.
    Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M et al. 2020. Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex. Nature 582:129–33
    [Google Scholar]
  65. 65.
    Fang D, Maldonado EN. 2018. VDAC regulation: a mitochondrial target to stop cell proliferation. Adv. Cancer Res. 138:41–69
    [Google Scholar]
  66. 66.
    Feno S, Rizzuto R, Raffaello A, Vecellio Reane D. 2021. The molecular complexity of the Mitochondrial Calcium Uniporter. Cell Calcium 93:102322
    [Google Scholar]
  67. 67.
    Fieni F, Johnson DE, Hudmon A, Kirichok Y. 2014. Mitochondrial Ca2+ uniporter and CaMKII in heart. Nature 513:E1–E2
    [Google Scholar]
  68. 68.
    Fieni F, Lee SB, Jan YN, Kirichok Y. 2012. Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat. Commun. 3:1317
    [Google Scholar]
  69. 69.
    Finichiu PG, James AM, Larsen L, Smith RA, Murphy MP. 2013. Mitochondrial accumulation of a lipophilic cation conjugated to an ionisable group depends on membrane potential, pH gradient and pK(a): implications for the design of mitochondrial probes and therapies. J. Bioenerget. Biomembr. 45:165–73
    [Google Scholar]
  70. 70.
    Foster DB, Ho AS, Rucker J, Garlid AO, Chen L et al. 2012. Mitochondrial ROMK channel is a molecular component of mitoK(ATP). Circ. Res. 111:446–54
    [Google Scholar]
  71. 71.
    Foster DB, Rucker JJ, Marbán E. 2008. Is Kir6.1 a subunit of mitoK(ATP)?. Biochem. Biophys. Res. Commun. 366:649–56
    [Google Scholar]
  72. 72.
    Frankenreiter S, Bednarczyk P, Kniess A, Bork NI, Straubinger J et al. 2017. cGMP-elevating compounds and ischemic conditioning provide cardioprotection against ischemia and reperfusion injury via cardiomyocyte-specific BK channels. Circulation 136:2337–55
    [Google Scholar]
  73. 73.
    Gałecka S, Kulawiak B, Bednarczyk P, Singh H, Szewczyk A. 2021. Single channel properties of mitochondrial large conductance potassium channel formed by BK-VEDEC splice variant. Sci. Rep. 11:10925
    [Google Scholar]
  74. 74.
    Gallio AE, Fung SS, Cammack-Najera A, Hudson AJ, Raven EL 2021. Understanding the logistics for the distribution of heme in cells. JACS Au 1:1541–55
    [Google Scholar]
  75. 75.
    Garg V, Suzuki J, Paranjpe I, Unsulangi T, Boyman L et al. 2021. The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter. eLife 10:e69312
    [Google Scholar]
  76. 76.
    Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P 2003. Mitochondrial potassium transport: the role of the mitochondrial ATP-sensitive K+ channel in cardiac function and cardioprotection. Biochim. Biophys. Acta 1606:1–21
    [Google Scholar]
  77. 77.
    Garlid KD, Paucek P. 2001. The mitochondrial potassium cycle. IUBMB Life 52:153–58
    [Google Scholar]
  78. 78.
    Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB et al. 1997. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ. Res. 81:1072–82
    [Google Scholar]
  79. 79.
    Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. 1996. The mitochondrial KATP channel as a receptor for potassium channel openers. J. Biol. Chem. 271:8796–99
    [Google Scholar]
  80. 80.
    Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F et al. 2013. Dimers of mitochondrial ATP synthase form the permeability transition pore. PNAS 110:5887–92
    [Google Scholar]
  81. 81.
    González-Sanabria N, Echeverría F, Segura I, Alvarado-Sánchez R, Latorre R. 2021. BK in double-membrane organelles: a biophysical, pharmacological, and functional survey. Front. Physiol. 12:761474
    [Google Scholar]
  82. 82.
    Grover GJ, D'Alonzo AJ, Garlid KD, Bajgar R, Lodge NJ et al. 2001. Pharmacologic characterization of BMS-191095, a mitochondrial K(ATP) opener with no peripheral vasodilator or cardiac action potential shortening activity. J. Pharmacol. Exp. Ther. 297:1184–92
    [Google Scholar]
  83. 83.
    Gupta A, Mahalakshmi R. 2019. Helix-strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3. J. Gen. Physiol. 151:489–504
    [Google Scholar]
  84. 84.
    Gururaja Rao S, Patel NJ, Singh H 2020. Intracellular chloride channels: novel biomarkers in diseases. Front. Physiol. 11:96
    [Google Scholar]
  85. 85.
    Gururaja Rao S, Ponnalagu D, Patel NJ, Singh H 2018. Three decades of chloride intracellular channel proteins: from organelle to organ physiology. Curr. Protoc. Pharmacol. 80:11.211–.17
    [Google Scholar]
  86. 86.
    Ham SJ, Lee D, Yoo H, Jun K, Shin H, Chung J 2020. Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. PNAS 117:4281–91
    [Google Scholar]
  87. 87.
    Ham SJ, Lee SY, Song S, Chung JR, Choi S, Chung J 2016. Interaction between RING1 (R1) and the ubiquitin-like (UBL) domains is critical for the regulation of Parkin activity. J. Biol. Chem. 291:1803–16
    [Google Scholar]
  88. 88.
    Hausenloy DJ, Schulz R, Girao H, Kwak BR, De Stefani D et al. 2020. Mitochondrial ion channels as targets for cardioprotection. J. Cell Mol. Med. 24:7102–14
    [Google Scholar]
  89. 89.
    Hawn MB, Akin E, Hartzell HC, Greenwood IA, Leblanc N. 2021. Molecular mechanisms of activation and regulation of ANO1-encoded Ca2+-activated Cl channels. Channels 15:569–603
    [Google Scholar]
  90. 90.
    Heinen A, Camara AK, Aldakkak M, Rhodes SS, Riess ML, Stowe DF. 2007. Mitochondrial Ca2+-induced K+ influx increases respiration and enhances ROS production while maintaining membrane potential. Am. J. Physiol. Cell Physiol. 292:C148–56
    [Google Scholar]
  91. 91.
    Heslop KA, Milesi V, Maldonado EN. 2021. VDAC modulation of cancer metabolism: advances and therapeutic challenges. Front. Physiol. 12:742839
    [Google Scholar]
  92. 92.
    Hosaka T, Okazaki M, Kimura-Someya T, Ishizuka-Katsura Y, Ito K et al. 2017. Crystal structural characterization reveals novel oligomeric interactions of human voltage-dependent anion channel 1. Protein Sci. 26:1749–58
    [Google Scholar]
  93. 93.
    Hunter DR, Haworth RA. 1979. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch. Biochem. Biophys. 195:453–59
    [Google Scholar]
  94. 94.
    Inoue I, Nagase H, Kishi K, Higuti T. 1991. ATP-sensitive K+ channel in the mitochondrial inner membrane. Nature 352:244–47
    [Google Scholar]
  95. 95.
    Jabůrek M, Yarov-Yarovoy V, Paucek P, Garlid KD. 1998. State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate. J. Biol. Chem. 273:13578–82
    [Google Scholar]
  96. 96.
    Joiner ML, Koval OM, Li J, He BJ, Allamargot C et al. 2012. CaMKII determines mitochondrial stress responses in heart. Nature 491:269–73
    [Google Scholar]
  97. 97.
    Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y et al. 2022. ATP synthase K+- and H+-fluxes drive ATP synthesis and enable mitochondrial K+-“uniporter” function: I. Characterization of ion fluxes. Function 3:zqab065
    [Google Scholar]
  98. 98.
    Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y et al. 2022. ATP synthase K+- and H+-fluxes drive ATP synthesis and enable mitochondrial K+-“uniporter” function: II. Ion and ATP synthase flux regulation. Function 3:zqac001
    [Google Scholar]
  99. 99.
    Kathiresan T, Harvey M, Orchard S, Sakai Y, Sokolowski B. 2009. A protein interaction network for the large conductance Ca2+-activated K+ channel in the mouse cochlea. Mol. Cell. Proteom. 8:1972–87
    [Google Scholar]
  100. 100.
    Khan A, Kuriachan G, Mahalakshmi R. 2021. Cellular interactome of mitochondrial voltage-dependent anion channels: oligomerization and channel (mis)regulation. ACS Chem. Neurosci. 12:3497–515
    [Google Scholar]
  101. 101.
    Kicinska A, Augustynek B, Kulawiak B, Jarmuszkiewicz W, Szewczyk A, Bednarczyk P. 2016. A large-conductance calcium-regulated K+ channel in human dermal fibroblast mitochondria. Biochem. J. 473:4457–71
    [Google Scholar]
  102. 102.
    Kicinska A, Kampa RP, Daniluk J, Sek A, Jarmuszkiewicz W et al. 2020. Regulation of the mitochondrial BKCa channel by the citrus flavonoid naringenin as a potential means of preventing cell damage. Molecules 25:3010
    [Google Scholar]
  103. 103.
    Kicinska A, Swida A, Bednarczyk P, Koszela-Piotrowska I, Choma K et al. 2007. ATP-sensitive potassium channel in mitochondria of the eukaryotic microorganism Acanthamoeba castellanii. J. Biol. Chem. 282:17433–41
    [Google Scholar]
  104. 104.
    Kinnally KW, Antonsson B. 2007. A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis 12:857–68
    [Google Scholar]
  105. 105.
    Kinnally KW, Campo ML, Tedeschi H. 1989. Mitochondrial channel activity studied by patch-clamping mitoplasts. J. Bioenerget. Biomembr. 21:497–506
    [Google Scholar]
  106. 106.
    Kirichok Y, Krapivinsky G, Clapham DE. 2004. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–64
    [Google Scholar]
  107. 107.
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J et al. 2004. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–65
    [Google Scholar]
  108. 108.
    Kominkova V, Malekova L, Tomaskova Z, Slezak P, Szewczyk A, Ondrias K. 2010. Modulation of intracellular chloride channels by ATP and Mg2+. Biochim. Biophys. Acta 1797:1300–12
    [Google Scholar]
  109. 109.
    Kon N, Murakoshi M, Isobe A, Kagechika K, Miyoshi N, Nagayama T. 2017. DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. Cell Death Discov 3:17045
    [Google Scholar]
  110. 110.
    König T, Tröder SE, Bakka K, Korwitz A, Richter-Dennerlein R et al. 2016. The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria. Mol. Cell 64:148–62
    [Google Scholar]
  111. 111.
    Krauskopf A, Eriksson O, Craigen WJ, Forte MA, Bernardi P. 2006. Properties of the permeability transition in VDAC1−/– mitochondria. Biochim. Biophys. Acta 1757:590–95
    [Google Scholar]
  112. 112.
    Kulawiak B, Bednarczyk P, Szewczyk A 2021. Multidimensional regulation of cardiac mitochondrial potassium channels. Cells 10:1554
    [Google Scholar]
  113. 113.
    Kulawiak B, Szewczyk A. 2022. Current challenges of mitochondrial potassium channel research. Front. Physiol. 13:907015
    [Google Scholar]
  114. 114.
    Laskowski M, Augustynek B, Bednarczyk P, Żochowska M, Kalisz J et al. 2019. Single-channel properties of the ROMK-pore-forming subunit of the mitochondrial ATP-sensitive potassium channel. Int. J. Mol. Sci. 20:5323
    [Google Scholar]
  115. 115.
    Laskowski M, Augustynek B, Kulawiak B, Koprowski P, Bednarczyk P et al. 2016. What do we not know about mitochondrial potassium channels?. Biochim. Biophys. Acta 1857:1247–57
    [Google Scholar]
  116. 116.
    Lawson K. 2000. Potassium channel openers as potential therapeutic weapons in ion channel disease. Kidney Int 57:838–45
    [Google Scholar]
  117. 117.
    Leanza L, Checchetto V, Biasutto L, Rossa A, Costa R et al. 2019. Pharmacological modulation of mitochondrial ion channels. Br. J. Pharmacol. 176:4258–83
    [Google Scholar]
  118. 118.
    Leanza L, Romio M, Becker KA, Azzolini M, Trentin L et al. 2017. Direct pharmacological targeting of a mitochondrial ion channel selectively kills tumor cells in vivo. Cancer Cell 31:516–31.e10
    [Google Scholar]
  119. 119.
    Leanza L, Venturini E, Kadow S, Carpinteiro A, Gulbins E, Becker KA. 2015. Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium 58:131–38
    [Google Scholar]
  120. 120.
    Leanza L, Zoratti M, Gulbins E, Szabo I. 2012. Induction of apoptosis in macrophages via Kv1.3 and Kv1.5 potassium channels. Curr. Med. Chem. 19:5394–404
    [Google Scholar]
  121. 121.
    Leanza L, Zoratti M, Gulbins E, Szabo I. 2014. Mitochondrial ion channels as oncological targets. Oncogene 33:5569–81
    [Google Scholar]
  122. 122.
    Lee AC, Xu X, Blachly-Dyson E, Forte M, Colombini M. 1998. The role of yeast VDAC genes on the permeability of the mitochondrial outer membrane. J. Membr. Biol. 161:173–81
    [Google Scholar]
  123. 123.
    León-Aparicio D, Salvador C, Aparicio-Trejo OE, Briones-Herrera A, Pedraza-Chaverri J et al. 2019. Novel potassium channels in kidney mitochondria: the hyperpolarization-activated and cyclic nucleotide-gated HCN channels. Int. J. Mol. Sci. 20:4995
    [Google Scholar]
  124. 124.
    Li W, Wilson GC, Bachmann M, Wang J, Mattarei A et al. 2022. Inhibition of a mitochondrial potassium channel in combination with gemcitabine and abraxane drastically reduces pancreatic ductal adenocarcinoma in an immunocompetent orthotopic murine model. Cancers 14:2618
    [Google Scholar]
  125. 125.
    Madreiter-Sokolowski CT, Klec C, Parichatikanond W, Stryeck S, Gottschalk B et al. 2016. PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells. Nat. Commun. 7:12897
    [Google Scholar]
  126. 126.
    Malinska D, Mirandola SR, Kunz WS. 2010. Mitochondrial potassium channels and reactive oxygen species. FEBS Lett 584:2043–48
    [Google Scholar]
  127. 127.
    Mallilankaraman K, Doonan P, Cárdenas C, Chandramoorthy HC, Müller M et al. 2012. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151:630–44
    [Google Scholar]
  128. 128.
    Manczak M, Sheiko T, Craigen WJ, Reddy PH. 2013. Reduced VDAC1 protects against Alzheimer's disease, mitochondria, and synaptic deficiencies. J. Alzheimer's Dis. 37:679–90
    [Google Scholar]
  129. 129.
    Mannella CA. 2021. VDAC-A primal perspective. Int. J. Mol. Sci. 22:1685
    [Google Scholar]
  130. 130.
    Márta K, Hasan P, Rodríguez-Prados M, Paillard M, Hajnóczky G. 2021. Pharmacological inhibition of the mitochondrial Ca2+ uniporter: relevance for pathophysiology and human therapy. J. Mol. Cell. Cardiol. 151:135–44
    [Google Scholar]
  131. 131.
    Martinucci S, Szabò I, Tombola F, Zoratti M. 2000. Ca2+-reversible inhibition of the mitochondrial megachannel by ubiquinone analogues. FEBS Lett 480:89–94
    [Google Scholar]
  132. 132.
    Matkovic K, Koszela-Piotrowska I, Jarmuszkiewicz W, Szewczyk A. 2011. Ion conductance pathways in potato tuber (Solanum tuberosum) inner mitochondrial membrane. Biochim. Biophys. Acta 1807:275–85
    [Google Scholar]
  133. 133.
    Matteucci A, Patron M, Vecellio Reane D, Gastaldello S, Amoroso S et al. 2018. Parkin-dependent regulation of the MCU complex component MICU1. Sci. Rep. 8:14199
    [Google Scholar]
  134. 134.
    Mertins B, Psakis G, Essen LO. 2014. Voltage-dependent anion channels: the wizard of the mitochondrial outer membrane. Biol. Chem. 395:1435–42
    [Google Scholar]
  135. 135.
    Mirzabekov T, Ballarin C, Nicolini M, Zatta P, Sorgato MC. 1993. Reconstitution of the native mitochondrial outer membrane in planar bilayers. Comparison with the outer membrane in a patch pipette and effect of aluminum compounds. J. Membr. Biol. 133:129–43
    [Google Scholar]
  136. 136.
    Misak A, Grman M, Malekova L, Novotova M, Markova J et al. 2013. Mitochondrial chloride channels: electrophysiological characterization and pH induction of channel pore dilation. Eur. Biophys. J. 42:709–20
    [Google Scholar]
  137. 137.
    Mise S, Matsumoto A, Shimada K, Hosaka T, Takahashi M et al. 2022. Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis. Nat. Commun. 13:1071
    [Google Scholar]
  138. 138.
    Mitchell P. 1991. Foundations of vectorial metabolism and osmochemistry. Biosci. Rep. 11:297–344
    [Google Scholar]
  139. 139.
    Mizushima W, Takahashi H, Watanabe M, Kinugawa S, Matsushima S et al. 2016. The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. J. Mol. Cell. Cardiol. 100:43–53
    [Google Scholar]
  140. 140.
    Naghdi S, Hajnóczky G. 2016. VDAC2-specific cellular functions and the underlying structure. Biochim. Biophys. Acta 1863:2503–14
    [Google Scholar]
  141. 141.
    Naghdi S, Varnai P, Hajnoczky G. 2015. Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. PNAS 112:E5590–99
    [Google Scholar]
  142. 142.
    Neginskaya MA, Pavlov EV, Sheu SS. 2021. Electrophysiological properties of the mitochondrial permeability transition pores: channel diversity and disease implication. Biochim. Biophys. Acta Bioenerget. 1862:148357
    [Google Scholar]
  143. 143.
    Nguyen NX, Armache JP, Lee C, Yang Y, Zeng W et al. 2018. Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559:570–74
    [Google Scholar]
  144. 144.
    Nickel AG, Kohlhaas M, Bertero E, Wilhelm D, Wagner M et al. 2020. CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes. J. Physiol. 598:1361–76
    [Google Scholar]
  145. 145.
    Novorolsky RJ, Nichols M, Kim JS, Pavlov EV, Woods JJ et al. 2020. The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury. J. Cerebral Blood Flow Metab. 40:1172–81
    [Google Scholar]
  146. 146.
    Ochoa SV, Otero L, Aristizabal-Pachon AF, Hinostroza F, Carvacho I, Torres YP. 2021. Hypoxic regulation of the large-conductance, calcium and voltage-activated potassium channel, BK. Front. Physiol 12:780206
    [Google Scholar]
  147. 147.
    Okazaki M, Kurabayashi K, Asanuma M, Saito Y, Dodo K, Sodeoka M. 2015. VDAC3 gating is activated by suppression of disulfide-bond formation between the N-terminal region and the bottom of the pore. Biochim. Biophys. Acta 1848:3188–96
    [Google Scholar]
  148. 148.
    O'Rourke B. 2007. Mitochondrial ion channels. Annu. Rev. Physiol. 69:19–49
    [Google Scholar]
  149. 149.
    O'Rourke B, Cortassa S, Aon MA. 2005. Mitochondrial ion channels: gatekeepers of life and death. Physiology 20:303–15
    [Google Scholar]
  150. 150.
    Orrenius S, Gogvadze V, Zhivotovsky B. 2015. Calcium and mitochondria in the regulation of cell death. Biochem. Biophys. Res. Commun. 460:72–81
    [Google Scholar]
  151. 151.
    O-Uchi J, Jhun BS, Xu S, Hurst S, Raffaello A et al. 2014. Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. Antioxidants Redox Signal 21:863–79
    [Google Scholar]
  152. 152.
    Oxenoid K, Dong Y, Cao C, Cui T, Sancak Y et al. 2016. Architecture of the mitochondrial calcium uniporter. Nature 533:269–73
    [Google Scholar]
  153. 153.
    Padilla-Flores T, López-González Z, Vaca L, Aparicio-Trejo OE, Briones-Herrera A et al. 2020. “Funny” channels in cardiac mitochondria modulate membrane potential and oxygen consumption. Biochem. Biophys. Res. Commun. 524:1030–36
    [Google Scholar]
  154. 154.
    Paggio A, Checchetto V, Campo A, Menabo R, Di Marco G et al. 2019. Identification of an ATP-sensitive potassium channel in mitochondria. Nature 572:609–13
    [Google Scholar]
  155. 155.
    Paillard M, Csordás G, Huang KT, Várnai P, SK Joseph, Hajnóczky G. 2018. MICU1 interacts with the D-ring of the MCU pore to control its Ca2+ flux and sensitivity to Ru360. Mol. Cell 72:778–85.e3
    [Google Scholar]
  156. 156.
    Pallafacchina G, Zanin S, Rizzuto R 2021. From the identification to the dissection of the physiological role of the mitochondrial calcium uniporter: an ongoing story. Biomolecules 11:786
    [Google Scholar]
  157. 157.
    Papanicolaou KN, Ashok D, Liu T, Bauer TM, Sun J et al. 2020. Global knockout of ROMK potassium channel worsens cardiac ischemia-reperfusion injury but cardiomyocyte-specific knockout does not: implications for the identity of mitoKATP. J. Mol. Cell. Cardiol. 139:176–89
    [Google Scholar]
  158. 158.
    Patil VM, Gupta SP. 2016. Studies on chloride channels and their modulators. Curr. Top. Med. Chem. 16:1862–76
    [Google Scholar]
  159. 159.
    Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D et al. 2014. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 53:726–37
    [Google Scholar]
  160. 160.
    Patron M, Granatiero V, Espino J, Rizzuto R, De Stefani D. 2019. MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake. Cell Death Differ 26:179–95
    [Google Scholar]
  161. 161.
    Paucek P, Mironova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. 1992. Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K+ channel from rat liver and beef heart mitochondria. J. Biol. Chem. 267:26062–69
    [Google Scholar]
  162. 162.
    Paucek P, Yarov-Yarovoy V, Sun X, Garlid KD. 1996. Inhibition of the mitochondrial KATP channel by long-chain acyl-CoA esters and activation by guanine nucleotides. J. Biol. Chem. 271:32084–88
    [Google Scholar]
  163. 163.
    Paventi G, Soldovieri MV, Servettini I, Barrese V, Miceli F et al. 2022. Kv7.4 channels regulate potassium permeability in neuronal mitochondria. Biochem. Pharmacol. 197:114931
    [Google Scholar]
  164. 164.
    Pereira O Jr., Kowaltowski AJ. 2021. Mitochondrial K+ transport: modulation and functional consequences. Molecules 26:2935
    [Google Scholar]
  165. 165.
    Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE et al. 2010. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467:291–96
    [Google Scholar]
  166. 166.
    Peruzzo R, Mattarei A, Azzolini M, Becker-Flegler KA, Romio M et al. 2020. Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family. Redox Biol 37:101705
    [Google Scholar]
  167. 167.
    Peruzzo R, Szabo I. 2019. Contribution of mitochondrial ion channels to chemo-resistance in cancer cells. Cancers 11:761
    [Google Scholar]
  168. 168.
    Phillips CB, Tsai CW, Tsai MF 2019. The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex. eLife 8:e41112
    [Google Scholar]
  169. 169.
    Pittalà MGG, Conti Nibali S, Reina S, Cunsolo V, Di Francesco A et al. 2021. VDACs post-translational modifications discovery by mass spectrometry: impact on their hub function. Int. J. Mol. Sci. 22:12833
    [Google Scholar]
  170. 170.
    Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L et al. 2013. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLOS ONE 8:e55785
    [Google Scholar]
  171. 171.
    Ponnalagu D, Gururaja Rao S, Farber J, Xin W, Hussain AT et al. 2016. Molecular identity of cardiac mitochondrial chloride intracellular channel proteins. Mitochondrion 27:6–14
    [Google Scholar]
  172. 172.
    Ponnalagu D, Hussain AT, Thanawala R, Meka J, Bednarczyk P et al. 2019. Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria. Life Sci 235:116841
    [Google Scholar]
  173. 173.
    Ponnalagu D, Singh H. 2017. Anion channels of mitochondria. Handb. Exp. Pharmacol. 240:71–101
    [Google Scholar]
  174. 174.
    Ponnalagu D, Singh H. 2020. Insights into the role of mitochondrial ion channels in inflammatory response. Front. Physiol. 11:258
    [Google Scholar]
  175. 175.
    Quast U, Guillon JM, Cavero I. 1994. Cellular pharmacology of potassium channel openers in vascular smooth muscle. Cardiovasc. Res. 28:805–10
    [Google Scholar]
  176. 176.
    Queralt-Martín M, Bergdoll L, Teijido O, Munshi N, Jacobs D et al. 2020. A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology. J. Gen. Physiol. 152:e201912501
    [Google Scholar]
  177. 177.
    Queralt-Martin M, Bergdoll LA, Abramson J, Jacobs D, Teijido Hermida O et al. 2019. Human VDAC3 forms VDAC1-type anionic channels that are high-conducting, permeable to metabolites, and regulated by cytosolic proteins. Biophys. J. 116:155a
    [Google Scholar]
  178. 178.
    Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G et al. 2013. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32:2362–76
    [Google Scholar]
  179. 179.
    Reina S, Checchetto V 2021. Voltage-dependent anion selective channel 3: unraveling structural and functional features of the least known porin isoform. Front. Physiol. 12:784867
    [Google Scholar]
  180. 180.
    Reina S, Checchetto V, Saletti R, Gupta A, Chaturvedi D et al. 2016. VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications. Oncotarget 7:2249–68
    [Google Scholar]
  181. 181.
    Reina S, Conti Nibali S, Tomasello MF, Magrì A, Messina A, De Pinto V 2022. Voltage dependent anion channel 3 (VDAC3) protects mitochondria from oxidative stress. Redox Biol 51:102264
    [Google Scholar]
  182. 182.
    Reina S, Guarino F, Magri A, De Pinto V. 2016. VDAC3 as a potential marker of mitochondrial status is involved in cancer and pathology. Front. Oncol. 6:264
    [Google Scholar]
  183. 183.
    Reina S, Pittalà MGG, Guarino F, Messina A, De Pinto V et al. 2020. Cysteine oxidations in mitochondrial membrane proteins: the case of VDAC isoforms in mammals. Front. Cell Dev. Biol. 8:397
    [Google Scholar]
  184. 184.
    Rizzuto R, De Stefani D, Raffaello A, Mammucari C. 2012. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol. 13:566–78
    [Google Scholar]
  185. 185.
    Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL et al. 2015. α-Synuclein shows high affinity interaction with voltage-dependent anion channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J. Biol. Chem. 290:18467–77
    [Google Scholar]
  186. 186.
    Rotko D, Bednarczyk P, Koprowski P, Kunz WS, Szewczyk A, Kulawiak B. 2020. Heme is required for carbon monoxide activation of mitochondrial BKCa channel. Eur. J. Pharmacol. 881:173191
    [Google Scholar]
  187. 187.
    Rotko D, Kunz WS, Szewczyk A, Kulawiak B. 2020. Signaling pathways targeting mitochondrial potassium channels. Int. J. Biochem. Cell Biol. 125:105792
    [Google Scholar]
  188. 188.
    Rusznák Z, Bakondi G, Kosztka L, Pocsai K, Dienes B et al. 2008. Mitochondrial expression of the two-pore domain TASK-3 channels in malignantly transformed and non-malignant human cells. Virchows Arch. 452:415–26
    [Google Scholar]
  189. 189.
    Ruy F, Vercesi AE, Andrade PB, Bianconi ML, Chaimovich H, Kowaltowski AJ. 2004. A highly active ATP-insensitive K+ import pathway in plant mitochondria. J. Bioenerget. Biomembr. 36:195–202
    [Google Scholar]
  190. 190.
    Ryu SY, Peixoto PM, Teijido O, Dejean LM, Kinnally KW. 2010. Role of mitochondrial ion channels in cell death. BioFactors 36:255–63
    [Google Scholar]
  191. 191.
    Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D et al. 2001. Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J. Biol. Chem. 276:39206–12
    [Google Scholar]
  192. 192.
    Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ et al. 2013. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379–82
    [Google Scholar]
  193. 193.
    Sassi N, De Marchi U, Fioretti B, Biasutto L, Gulbins E et al. 2010. An investigation of the occurrence and properties of the mitochondrial intermediate-conductance Ca2+-activated K+ channel mtKCa3.1. Biochim. Biophys. Acta 1797:1260–67
    [Google Scholar]
  194. 194.
    Sato T, Marbán E. 2000. The role of mitochondrial K(ATP) channels in cardioprotection. Basic Res. Cardiol. 95:285–89
    [Google Scholar]
  195. 195.
    Sayeed I, Parvez S, Winkler-Stuck K, Seitz G, Trieu I et al. 2006. Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2-receptor agonist pramipexole. FASEB J. 20:556–58
    [Google Scholar]
  196. 196.
    Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D et al. 2005. Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol. Pharmacol. 68:1254–70
    [Google Scholar]
  197. 197.
    Schredelseker J, Paz A, López CJ, Altenbach C, Leung CS et al. 2014. High resolution structure and double electron-electron resonance of the zebrafish voltage-dependent anion channel 2 reveal an oligomeric population. J. Biol. Chem. 289:12566–77
    [Google Scholar]
  198. 198.
    Sek A, Kampa RP, Kulawiak B, Szewczyk A, Bednarczyk P. 2021. Identification of the large-conductance Ca2+-regulated potassium channel in mitochondria of human bronchial epithelial cells. Molecules 26:3233
    [Google Scholar]
  199. 199.
    Severin F, Urbani A, Varanita T, Bachmann M, Azzolini M et al. 2022. Pharmacological modulation of Kv1.3 potassium channel selectively triggers pathological B lymphocyte apoptosis in vivo in a genetic CLL model. J. Exp. Clin. Cancer Res. 41:64
    [Google Scholar]
  200. 200.
    Shanmughapriya S, Rajan S, Hoffman NE, Higgins AM, Tomar D et al. 2015. SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol. Cell 60:47–62
    [Google Scholar]
  201. 201.
    Shimizu H, Huber S, Langenbacher AD, Crisman L, Huang J et al. 2021. Glutamate 73 promotes anti-arrhythmic effects of voltage-dependent anion channel through regulation of mitochondrial Ca2+ uptake. Front. Physiol. 12:724828
    [Google Scholar]
  202. 202.
    Shoshan-Barmatz V, Shteinfer-Kuzmine A, Verma A. 2020. VDAC1 at the intersection of cell metabolism, apoptosis, and diseases. Biomolecules 10:1485
    [Google Scholar]
  203. 203.
    Siemen D, Loupatatzis C, Borecky J, Gulbins E, Lang F. 1999. Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. Biochem. Biophys. Res. Commun. 257:549–54
    [Google Scholar]
  204. 204.
    Silic-Benussi M, Scattolin G, Cavallari I, Minuzzo S, Del Bianco P et al. 2018. Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis. Cell Death Dis 9:822
    [Google Scholar]
  205. 205.
    Singh H. 2021. Mitochondrial ion channels in cardiac function. Am. J. Physiol. Cell Physiol. 321:C812–25
    [Google Scholar]
  206. 206.
    Singh H, Lu R, Bopassa JC, Meredith AL, Stefani E, Toro L 2013. MitoBKCa is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location. PNAS 110:10836–41
    [Google Scholar]
  207. 207.
    Skalska J, Bednarczyk P, Piwońska M, Kulawiak B, Wilczynski G et al. 2009. Calcium ions regulate K+ uptake into brain mitochondria: the evidence for a novel potassium channel. Int. J. Mol. Sci. 10:1104–20
    [Google Scholar]
  208. 208.
    Skalska J, Piwońska M, Wyroba E, Surmacz L, Wieczorek R et al. 2008. A novel potassium channel in skeletal muscle mitochondria. Biochim. Biophys. Acta 1777:651–59
    [Google Scholar]
  209. 209.
    Smith RA, Hartley RC, Murphy MP. 2011. Mitochondria-targeted small molecule therapeutics and probes. Antioxidants Redox Signal 15:3021–38
    [Google Scholar]
  210. 210.
    Soltysinska E, Bentzen BH, Barthmes M, Hattel H, Thrush AB et al. 2014. KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury. PLOS ONE 9:e103402
    [Google Scholar]
  211. 211.
    Sorgato MC, Keller BU, Stühmer W. 1987. Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel. Nature 330:498–500
    [Google Scholar]
  212. 212.
    Stowe DF, Gadicherla AK, Zhou Y, Aldakkak M, Cheng Q et al. 2013. Protection against cardiac injury by small Ca2+-sensitive K+ channels identified in guinea pig cardiac inner mitochondrial membrane. Biochim. Biophys. Acta 1828:427–42
    [Google Scholar]
  213. 213.
    Strickland M, Yacoubi-Loueslati B, Bouhaouala-Zahar B, Pender SLF, Larbi A. 2019. Relationships between ion channels, mitochondrial functions and inflammation in human aging. Front. Physiol. 10:158
    [Google Scholar]
  214. 214.
    Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L. 2012. Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J. Biol. Chem. 287:40652–60
    [Google Scholar]
  215. 215.
    Sun Y, Yang YM, Hu YY, Ouyang L, Sun ZH et al. 2022. Inhibition of nuclear deacetylase Sirtuin-1 induces mitochondrial acetylation and calcium overload leading to cell death. Redox Biol 53:102334
    [Google Scholar]
  216. 216.
    Szabo I, Bernardi P, Zoratti M. 1992. Modulation of the mitochondrial megachannel by divalent cations and protons. J. Biol. Chem. 267:2940–46
    [Google Scholar]
  217. 217.
    Szabo I, Bock J, Grassme H, Soddemann M, Wilker B et al. 2008. Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. PNAS 105:14861–66
    [Google Scholar]
  218. 218.
    Szabo I, Bock J, Jekle A, Soddemann M, Adams C et al. 2005. A novel potassium channel in lymphocyte mitochondria. J. Biol. Chem. 280:12790–98
    [Google Scholar]
  219. 219.
    Szabo I, Zoratti M. 1991. The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J. Biol. Chem. 266:3376–79
    [Google Scholar]
  220. 220.
    Szabo I, Zoratti M. 2014. Mitochondrial channels: ion fluxes and more. Physiol. Rev. 94:519–608
    [Google Scholar]
  221. 221.
    Szabo I, Zoratti M, Biasutto L. 2020. Targeting mitochondrial ion channels for cancer therapy. Redox Biol 42:101846
    [Google Scholar]
  222. 222.
    Szewczyk A, Marbán E. 1999. Mitochondria: a new target for K+ channel openers. Trends Pharmacol. Sci. 20:157–61
    [Google Scholar]
  223. 223.
    Szewczyk A, Mikołajek B, Pikuła S, Nałecz MJ. 1993. Potassium channel openers induce mitochondrial matrix volume changes via activation of ATP-sensitive K+ channel. Pol. J. Pharmacol. 45:437–43
    [Google Scholar]
  224. 224.
    Szewczyk A, Skalska J, Glab M, Kulawiak B, Malinska D et al. 2006. Mitochondrial potassium channels: from pharmacology to function. Biochim. Biophys. Acta 1757:715–20
    [Google Scholar]
  225. 225.
    Szewczyk A, Wójcik G, Lobanov NA, Nałecz MJ. 1997. The mitochondrial sulfonylurea receptor: identification and characterization. Biochem. Biophys. Res. Commun. 230:611–15
    [Google Scholar]
  226. 226.
    Szteyn K, Singh H. 2020. BKCa channels as targets for cardioprotection. Antioxidants 9:760
    [Google Scholar]
  227. 227.
    Teardo E, Carraretto L, Moscatiello R, Cortese E, Vicario M et al. 2019. A chloroplast-localized mitochondrial calcium uniporter transduces osmotic stress in Arabidopsis. Nat. Plants 5:581–88
    [Google Scholar]
  228. 228.
    Teardo E, Carraretto L, Wagner S, Formentin E, Behera S et al. 2017. Physiological characterization of a plant mitochondrial calcium uniporter in vitro and in vivo. Plant Physiol 173:1355–70
    [Google Scholar]
  229. 229.
    Testai L, Barrese V, Soldovieri MV, Ambrosino P, Martelli A et al. 2016. Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection. Cardiovasc. Res. 110:40–50
    [Google Scholar]
  230. 230.
    Testai L, Rapposelli S, Martelli A, Breschi MC, Calderone V. 2015. Mitochondrial potassium channels as pharmacological target for cardioprotective drugs. Med. Res. Rev. 35:520–53
    [Google Scholar]
  231. 231.
    Thiede A, Gellerich FN, Schönfeld P, Siemen D. 2012. Complex effects of 17β-estradiol on mitochondrial function. Biochim. Biophys. Acta 1817:1747–53
    [Google Scholar]
  232. 232.
    Tinker A, Aziz Q, Li Y, Specterman M. 2018. ATP-sensitive potassium channels and their physiological and pathophysiological roles. Compr. Physiol. 8:1463–511
    [Google Scholar]
  233. 233.
    Toczyłowska-Mamińska R, Olszewska A, Laskowski M, Bednarczyk P, Skowronek K, Szewczyk A. 2014. Potassium channel in the mitochondria of human keratinocytes. J. Investig. Dermatol. 134:764–72
    [Google Scholar]
  234. 234.
    Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y et al. 2016. Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. eLife 5:e15545
    [Google Scholar]
  235. 235.
    Ujwal R, Cascio D, Colletier JP, Faham S, Zhang J et al. 2008. The crystal structure of mouse VDAC1 at 2.3 Å resolution reveals mechanistic insights into metabolite gating. PNAS 105:17742–47
    [Google Scholar]
  236. 236.
    Urbani A, Giorgio V, Carrer A, Franchin C, Arrigoni G et al. 2019. Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore. Nat. Commun. 10:4341
    [Google Scholar]
  237. 237.
    Urbani A, Prosdocimi E, Carrer A, Checchetto V, Szabò I. 2020. Mitochondrial ion channels of the inner membrane and their regulation in cell death signaling. Front. Cell Dev. Biol. 8:620081
    [Google Scholar]
  238. 238.
    Vais H, Mallilankaraman K, Mak DO, Hoff H, Payne R et al. 2016. EMRE is a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter. Cell Rep 14:403–10
    [Google Scholar]
  239. 239.
    Vais H, Payne R, Paudel U, Li C, Foskett JK. 2020. Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca2+ uptake. PNAS 117:21731–39
    [Google Scholar]
  240. 240.
    Varughese JT, Buchanan SK, Pitt AS 2021. The role of voltage-dependent anion channel in mitochondrial dysfunction and human disease. Cells 10:1737
    [Google Scholar]
  241. 241.
    Vecellio Reane D, Vallese F, Checchetto V, Acquasaliente L, Butera G et al. 2016. A MICU1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle. Mol. Cell 64:760–73
    [Google Scholar]
  242. 242.
    Verkman AS, Galietta LJ. 2009. Chloride channels as drug targets. Nat. Rev. Drug Discov. 8:153–71
    [Google Scholar]
  243. 243.
    Walewska A, Szewczyk A, Krajewska M, Koprowski P. 2022. Targeting mitochondrial large-conductance calcium-activated potassium channel by hydrogen sulfide via heme-binding site. J. Pharmacol. Exp. Ther. 381:137–50
    [Google Scholar]
  244. 244.
    Wang H, An J, He S, Liao C, Wang J, Tuo B 2021. Chloride intracellular channels as novel biomarkers for digestive system tumors (review). Mol. Med. Rep. 24:630
    [Google Scholar]
  245. 245.
    Wang Y, Haider HK, Ahmad N, Ashraf M. 2005. Mechanisms by which K(ATP) channel openers produce acute and delayed cardioprotection. Vasc. Pharmacol. 42:253–64
    [Google Scholar]
  246. 246.
    Wang Y, Han Y, She J, Nguyen NX, Mootha VK et al. 2020. Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter. eLife 9:e60513
    [Google Scholar]
  247. 247.
    Watanabe A, Maeda K, Nara A, Hashida M, Ozono M et al. 2022. Quantitative analysis of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) in mitochondria from mouse tissues and HeLa cells. FEBS Open Bio 12:811–26
    [Google Scholar]
  248. 248.
    Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL et al. 2002. The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J. Biol. Chem. 277:18891–97
    [Google Scholar]
  249. 249.
    Wojtovich AP, Burwell LS, Sherman TA, Nehrke KW, Brookes PS. 2008. The C. elegans mitochondrial K+(ATP) channel: a potential target for preconditioning. Biochem. Biophys. Res. Commun. 376:625–28
    [Google Scholar]
  250. 250.
    Wojtovich AP, Sherman TA, Nadtochiy SM, Urciuoli WR, Brookes PS, Nehrke K. 2011. SLO-2 is cytoprotective and contributes to mitochondrial potassium transport. PLOS ONE 6:e28287
    [Google Scholar]
  251. 251.
    Wojtovich AP, Smith CO, Urciuoli WR, Wang YT, Xia X-M et al. 2016. Cardiac Slo2.1 is required for volatile anesthetic stimulation of K+ transport and anesthetic preconditioning. Anesthesiology 124:1065–76
    [Google Scholar]
  252. 252.
    Woods JJ, Nemani N, Shanmughapriya S, Kumar A, Zhang M et al. 2019. A selective and cell-permeable mitochondrial calcium uniporter (MCU) inhibitor preserves mitochondrial bioenergetics after hypoxia/reoxygenation injury. ACS Central Sci 5:153–66
    [Google Scholar]
  253. 253.
    Wrzosek A, Augustynek B, Żochowska M, Szewczyk A 2020. Mitochondrial potassium channels as druggable targets. Biomolecules 10:1200
    [Google Scholar]
  254. 254.
    Wrzosek A, Gałecka S, Żochowska M, Olszewska A, Kulawiak B. 2022. Alternative targets for modulators of mitochondrial potassium channels. Molecules 27:299
    [Google Scholar]
  255. 255.
    Wunder UR, Colombini M. 1991. Patch clamping VDAC in liposomes containing whole mitochondrial membranes. J. Membr. Biol. 123:83–91
    [Google Scholar]
  256. 256.
    Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE et al. 2002. Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science 298:1029–33
    [Google Scholar]
  257. 257.
    Xu X, Decker W, Sampson MJ, Craigen WJ, Colombini M. 1999. Mouse VDAC isoforms expressed in yeast: channel properties and their roles in mitochondrial outer membrane permeability. J. Membr. Biol. 170:89–102
    [Google Scholar]
  258. 258.
    Yao J, McHedlishvili D, McIntire WE, Guagliardo NA, Erisir A et al. 2017. Functional TASK-3-like channels in mitochondria of aldosterone-producing zona glomerulosa cells. Hypertension 70:347–56
    [Google Scholar]
  259. 259.
    Zhang DX, Chen YF, Campbell WB, Zou AP, Gross GJ, Li PL. 2001. Characteristics and superoxide-induced activation of reconstituted myocardial mitochondrial ATP-sensitive potassium channels. Circ. Res. 89:1177–83
    [Google Scholar]
  260. 260.
    Zhang HY, McPherson BC, Liu H, Baman TS, Rock P, Yao Z. 2002. H2O2 opens mitochondrial K(ATP) channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 282:H1395–403
    [Google Scholar]
  261. 261.
    Zhang J, Li M, Zhang Z, Zhu R, Olcese R et al. 2017. The mitochondrial BKCa channel cardiac interactome reveals BKCa association with the mitochondrial import receptor subunit Tom22, and the adenine nucleotide translocator. Mitochondrion 33:84–101
    [Google Scholar]
  262. 262.
    Zhuo W, Zhou H, Guo R, Yi J, Zhang L et al. 2021. Structure of intact human MCU supercomplex with the auxiliary MICU subunits. Protein Cell 12:220–29
    [Google Scholar]
  263. 263.
    Zinghirino F, Pappalardo XG, Messina A, Guarino F, De Pinto V. 2020. Is the secret of VDAC isoforms in their gene regulation? Characterization of human VDAC genes expression profile, promoter activity, and transcriptional regulators. Int. J. Mol. Sci. 21:7388
    [Google Scholar]
  264. 264.
    Zoratti M, De Marchi U, Biasutto L, Szabò I. 2010. Electrophysiology clarifies the megariddles of the mitochondrial permeability transition pore. FEBS Lett 584:1997–2004
    [Google Scholar]
  265. 265.
    Zoratti M, Szabo I. 1995. The mitochondrial permeability transition. Biochim. Biophys. Acta 1241:139–76
    [Google Scholar]
  266. 266.
    Zou L, Linck V, Zhai YJ, Galarza-Paez L, Li L et al. 2018. Knockout of mitochondrial voltage-dependent anion channel type 3 increases reactive oxygen species (ROS) levels and alters renal sodium transport. J. Biol. Chem. 293:1666–75
    [Google Scholar]
/content/journals/10.1146/annurev-biophys-092622-094853
Loading
/content/journals/10.1146/annurev-biophys-092622-094853
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error