Skip to main content
SpringerLink
Log in
Book cover

Proteases in Health and Disease pp 21–32Cite as

Mitochondrial Calpains: Who, What, Where, When and Why?

  • Chapter
  • First Online:

  • 1124 Accesses

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 7))

Abstract

Evidence accumulated over the past two decades has clearly demonstrated that one or more calpains are localized to mitochondria. This evidence includes mitochondrial calpain activity, immunoreactivity, purification, and N-terminal sequencing. Supporting data is greatest for CAPN1 and CAPN10, although the support for mitochondrial CAPN2 is also compelling. The mitochondrial localization of calpains may protect them from CAST inhibition, and also expose the proteases to Ca2+ transients during mitochondrial Ca2+ accumulation and/or opening of the mitochondrial permeability transition pore. One suggestion is that calpain activation may be required for mitochondrial permeability transition, with much stronger evidence demonstrating calpain activation in the aftermath of permeability transition pore opening. Several putative substrates of mitochondrial calpains have been identified, with the greatest attention paid to apoptosis inducing factor. Although much data are consistent with the involvement of mitochondrial CAPN1 activation in the processing and release of apoptosis inducing factor, there are also contrasting data. All mitochondrial calpains identified to date are also present in the cytosol, making selective mitochondrial inhibition or knockdown difficult and complicating analysis of mitochondrial calpains. Calpains are clearly present in mitochondria, much work remains to identify their substrates and physiological and pathological roles.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Friedrich P, Bozoky Z (2005) Digestive versus regulatory proteases: on calpain action in vivo. Biol Chem 386:609–612

    Article  PubMed  CAS  Google Scholar 

  2. Ono Y, Sorimachi H (2012) Calpains: an elaborate proteolytic system. Biochim Biophys Acta 1824:224–236

    Article  PubMed  CAS  Google Scholar 

  3. De Martino GN (1981) Calcium-dependent proteolytic activity in rat liver: identification of two proteases with different calcium requirements. Arch Biochem Biophys 211:253–257

    Article  PubMed  Google Scholar 

  4. Mellgren RL (1980) Canine cardiac calcium-dependent proteases: resolution of two forms with different requirements for calcium. FEBS Lett 109:129–133

    Article  PubMed  CAS  Google Scholar 

  5. Murachi T, Tanaka K, Hatanaka M et al (1980) Intracellular Ca2+-dependent protease (calpain) and its high-molecular-weight endogenous inhibitor (calpastatin). Adv Enzyme Regul 19: 407–424

    Article  PubMed  CAS  Google Scholar 

  6. Guroff G (1964) A neutral, calcium-activated proteinase from the soluble fraction of Rat brain. J Biol Chem 239:149–155

    PubMed  CAS  Google Scholar 

  7. Goll DE, Thompson VF, Li H et al (2003) The calpain system. Physiol Rev 83:731–801

    PubMed  CAS  Google Scholar 

  8. Suzuki K, Hata S, Kawabata Y et al (2004) Structure, activation, and biology of calpain. Diabetes 53(Suppl 1):S12–S18

    Article  PubMed  CAS  Google Scholar 

  9. Thompson VF, Goll DE (2000) Purification of mu-calpain, m-calpain, and calpastatin from animal tissues. Methods Mol Biol 144:3–16

    PubMed  CAS  Google Scholar 

  10. Wendt A, Thompson VF, Goll DE (2004) Interaction of calpastatin with calpain: a review. Biol Chem 385:465–472

    Article  PubMed  CAS  Google Scholar 

  11. Beer DG, Hjelle JJ, Petersen DR et al (1982) Calcium-activated proteolytic activity in rat liver mitochondria. Biochem Biophys Res Commun 109:1276–1283

    Article  PubMed  CAS  Google Scholar 

  12. Kumamoto T, Kleese WC, Cong JY et al (1992) Localization of the Ca(2+)-dependent proteinases and their inhibitor in normal, fasted, and denervated rat skeletal muscle. Anat Rec 232:60–77

    Article  PubMed  CAS  Google Scholar 

  13. Mori M, Miura S, Tatibana M et al (1980) Characterization of a protease apparently involved in processing of pre-ornithine transcarbamylase of rat liver. Proc Natl Acad Sci U S A 77:7044–7048

    Article  PubMed  CAS  Google Scholar 

  14. Tavares A, Duque-Magalhaes MC (1991) Demonstration of three calpains in the matrix of rat liver mitochondria. Biomed Biochim Acta 50:523–529

    PubMed  CAS  Google Scholar 

  15. Endo S, Ishiguro S, Tamai M (1999) Possible mechanism for the decrease of mitochondrial aspartate aminotransferase activity in ischemic and hypoxic rat retinas. Biochim Biophys Acta 1450:385–396

    Article  PubMed  CAS  Google Scholar 

  16. Baudry M, DuBrin R, Lynch G (1987) Subcellular compartmentalization of calcium-dependent and calcium-independent neutral proteases in brain. Synapse 1:506–511

    Article  PubMed  CAS  Google Scholar 

  17. Chakrabarti AK, Yoshida Y, Powers JM et al (1988) Calcium-activated neutral proteinase in rat brain myelin and subcellular fractions. J Neurosci Res 20:351–358

    Article  PubMed  CAS  Google Scholar 

  18. Daniel KG, Anderson JS, Zhong Q et al (2003) Association of mitochondrial calpain activation with increased expression and autolysis of calpain small subunit in an early stage of apoptosis. Int J Mol Med 12:247–252

    PubMed  CAS  Google Scholar 

  19. Gao G, Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J Cell Biochem 80:53–72

    Article  PubMed  CAS  Google Scholar 

  20. Polster BM, Basanez G, Etxebarria A et al (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem 280:6447–6454

    Article  PubMed  CAS  Google Scholar 

  21. Gores GJ, Miyoshi H, Botla R et al (1998) Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases. Biochim Biophys Acta 1366:167–175

    Article  PubMed  CAS  Google Scholar 

  22. Arnoult D, Akarid K, Grodet A et al (2002) On the evolution of programmed cell death: apoptosis of the unicellular eukaryote Leishmania major involves cysteine proteinase activation and mitochondrion permeabilization. Cell Death Differ 9:65–81

    Article  PubMed  CAS  Google Scholar 

  23. Okonkwo DO, Buki A, Siman R et al (1999) Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 10:353–358

    Article  PubMed  CAS  Google Scholar 

  24. Ding WX, Shen HM, Ong CN (2002) Calpain activation after mitochondrial permeability transition in microcystin-induced cell death in rat hepatocytes. Biochem Biophys Res Commun 291:321–331

    Article  PubMed  CAS  Google Scholar 

  25. Ferrand-Drake M, Zhu C, Gido G et al (2003) Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis-inducing factor, cytochrome c and caspase-3 activation in neurons exposed to transient hypoglycemia. J Neurochem 85:1431–1442

    Article  PubMed  CAS  Google Scholar 

  26. Liu X, Van Vleet T, Schnellmann RG (2004) The role of calpain in oncotic cell death. Annu Rev Pharmacol Toxicol 44:349–370

    Article  PubMed  CAS  Google Scholar 

  27. Garcia M, Bondada V, Geddes JW (2005) Mitochondrial localization of mu-calpain. Biochem Biophys Res Commun 338:1241–1247

    Article  PubMed  CAS  Google Scholar 

  28. Badugu R, Garcia M, Bondada V et al (2008) N terminus of calpain 1 is a mitochondrial targeting sequence. J Biol Chem 283:3409–3417

    Article  PubMed  CAS  Google Scholar 

  29. Aoki K, Imajoh S, Ohno S et al (1986) Complete amino acid sequence of the large subunit of the low-Ca2+-requiring form of human Ca2+-activated neutral protease (muCANP) deduced from its cDNA sequence. FEBS Lett 205:313–317

    Article  PubMed  CAS  Google Scholar 

  30. Herrmann JM, Hell K (2005) Chopped, trapped or tacked–protein translocation into the IMS of mitochondria. Trends Biochem Sci 30:205–211

    Article  PubMed  CAS  Google Scholar 

  31. Kar P, Chakraborti T, Roy S et al (2007) Identification of calpastatin and mu-calpain and studies of their association in pulmonary smooth muscle mitochondria. Arch Biochem Biophys 466:290–299

    Article  PubMed  CAS  Google Scholar 

  32. Kar P, Chakraborti T, Samanta K et al (2008) Submitochondrial localization of associated mu-calpain and calpastatin. Arch Biochem Biophys 470:176–186

    Article  PubMed  CAS  Google Scholar 

  33. Kar P, Samanta K, Shaikh S et al (2010) Mitochondrial calpain system: an overview. Arch Biochem Biophys 495:1–7

    Article  PubMed  CAS  Google Scholar 

  34. Ozaki T, Tomita H, Tamai M et al (2007) Characteristics of mitochondrial calpains. J Biochem 142:365–376

    Article  PubMed  CAS  Google Scholar 

  35. Ozaki T, Yamashita T, Ishiguro S (2008) ERp57-associated mitochondrial micro-calpain truncates apoptosis-inducing factor. Biochim Biophys Acta 1783:1955–1963

    Article  PubMed  CAS  Google Scholar 

  36. Ozaki T, Yamashita T, Ishiguro S (2009) Mitochondrial m-calpain plays a role in the release of truncated apoptosis-inducing factor from the mitochondria. Biochim Biophys Acta 1793: 1848–1859

    Article  PubMed  CAS  Google Scholar 

  37. Ozaki T, Yamashita T, Ishiguro S (2011) Ca(2)+-induced release of mitochondrial m-calpain from outer membrane with binding of calpain small subunit and Grp75. Arch Biochem Biophys 507:254–261

    Article  PubMed  CAS  Google Scholar 

  38. Arrington DD, Van Vleet TR, Schnellmann RG (2006) Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Am J Physiol Cell Physiol 291:C1159–C1171

    Article  PubMed  CAS  Google Scholar 

  39. Giguere CJ, Covington MD, Schnellmann RG (2008) Mitochondrial calpain 10 activity and expression in the kidney of multiple species. Biochem Biophys Res Commun 366:258–262

    Article  PubMed  CAS  Google Scholar 

  40. Covington MD, Arrington DD, Schnellmann RG (2009) Calpain 10 is required for cell viability and is decreased in the aging kidney. Am J Physiol Renal Physiol 296:F478–F486

    Article  PubMed  CAS  Google Scholar 

  41. Rasbach KA, Arrington DD, Odejinmi S et al (2009) Identification and optimization of a novel inhibitor of mitochondrial calpain 10. J Med Chem 52:181–188

    Article  PubMed  CAS  Google Scholar 

  42. Tremper-Wells B, Vallano ML (2005) Nuclear calpain regulates Ca2+-dependent signaling via proteolysis of nuclear Ca2+/calmodulin-dependent protein kinase type IV in cultured neurons. J Biol Chem 280:2165–2175

    Article  PubMed  CAS  Google Scholar 

  43. Gil-Parrado S, Popp O, Knoch TA et al (2003) Subcellular localization and in vivo subunit interactions of ubiquitous mu-calpain. J Biol Chem 278:16336–16346

    Article  PubMed  CAS  Google Scholar 

  44. Hood JL, Brooks WH, Roszman TL (2004) Differential compartmentalization of the calpain/calpastatin network with the endoplasmic reticulum and Golgi apparatus. J Biol Chem 279:43126–43135

    Article  PubMed  CAS  Google Scholar 

  45. Hood JL, Logan BB, Sinai AP et al (2003) Association of the calpain/calpastatin network with subcellular organelles. Biochem Biophys Res Commun 310:1200–1212

    Article  PubMed  CAS  Google Scholar 

  46. Otera H, Ohsakaya S, Nagaura Z et al (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24:1375–1386

    Article  PubMed  CAS  Google Scholar 

  47. Norberg E, Orrenius S, Zhivotovsky B (2010) Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun 396:95–100

    Article  PubMed  CAS  Google Scholar 

  48. Hangen E, Blomgren K, Benit P et al (2010) Life with or without AIF. Trends Biochem Sci 35:278–287

    Article  PubMed  CAS  Google Scholar 

  49. Susin SA, Lorenzo HK, Zamzami N et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446

    Article  PubMed  CAS  Google Scholar 

  50. Cande C, Vahsen N, Garrido C et al (2004) Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 11:591–595

    PubMed  CAS  Google Scholar 

  51. Min KS, Terano Y, Onosaka S et al (1992) Induction of metallothionein synthesis by menadione or carbon tetrachloride is independent of free radical production. Toxicol Appl Pharmacol 113:74–79

    Article  PubMed  CAS  Google Scholar 

  52. Norberg E, Gogvadze V, Ott M et al (2008) An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death. Cell Death Differ 15:1857–1864

    Article  PubMed  CAS  Google Scholar 

  53. Cao G, Xing J, Xiao X et al (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27:9278–9293

    Article  PubMed  CAS  Google Scholar 

  54. Vosler PS, Sun D, Wang S et al (2009) Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways. Exp Neurol 218: 213–220

    Article  PubMed  CAS  Google Scholar 

  55. Liu L, Xing D, Chen WR (2009) Micro-calpain regulates caspase-dependent and apoptosis inducing factor-mediated caspase-independent apoptotic pathways in cisplatin-induced apoptosis. Int J Cancer 125:2757–2766

    Article  PubMed  CAS  Google Scholar 

  56. Chaitanya GV, Babu PP (2008) Multiple apoptogenic proteins are involved in the nuclear translocation of Apoptosis Inducing Factor during transient focal cerebral ischemia in rat. Brain Res 1246:178–190

    Article  PubMed  CAS  Google Scholar 

  57. Joshi A, Bondada V, Geddes JW (2009) Mitochondrial micro-calpain is not involved in the processing of apoptosis-inducing factor. Exp Neurol 218:221–227

    Article  PubMed  CAS  Google Scholar 

  58. Yuste VJ, Moubarak RS, Delettre C et al (2005) Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ 12:1445–1448

    Article  PubMed  CAS  Google Scholar 

  59. Wang Y, Kim NS, Li X et al (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110:687–696

    Article  PubMed  CAS  Google Scholar 

  60. Ott M, Norberg E, Zhivotovsky B et al (2009) Mitochondrial targeting of tBid/Bax: a role for the TOM complex? Cell Death Differ 16:1075–1082

    Article  PubMed  CAS  Google Scholar 

  61. Korsmeyer SJ, Wei MC, Saito M et al (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173

    Article  PubMed  CAS  Google Scholar 

  62. Shulga N, Pastorino JG (2006) Acyl coenzyme A-binding protein augments bid-induced mitochondrial damage and cell death by activating mu-calpain. J Biol Chem 281:30824–30833

    Article  PubMed  CAS  Google Scholar 

  63. Kar P, Chakraborti T, Samanta K et al (2009) mu-Calpain mediated cleavage of the Na+/Ca2+ exchanger in isolated mitochondria under A23187 induced Ca2+ stimulation. Arch Biochem Biophys 482:66–76

    Article  PubMed  CAS  Google Scholar 

  64. Jahani-Asl A, Pilon-Larose K, Xu W et al (2011) The mitochondrial inner membrane GTPase, optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity. J Biol Chem 286:4772–4782

    Article  PubMed  CAS  Google Scholar 

  65. Galluzzi L, Vitale I, Abrams JM et al (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120

    Article  PubMed  CAS  Google Scholar 

  66. Wang KK (2000) Calpain and caspase: can you tell the difference? Trends Neurosci 23:20–26

    Article  PubMed  Google Scholar 

  67. Syntichaki P, Xu K, Driscoll M et al (2002) Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419:939–944

    Article  PubMed  CAS  Google Scholar 

  68. Li Y, Bondada V, Joshi A et al (2009) Calpain 1 and Calpastatin expression is developmentally regulated in rat brain. Exp Neurol 220:316–319

    Article  PubMed  CAS  Google Scholar 

  69. Michaelis ML, Seyb KI, Ansar S (2005) Cytoskeletal integrity as a drug target. Curr Alzheimer Res 2:227–229

    Article  PubMed  CAS  Google Scholar 

  70. Bano D, Young KW, Guerin CJ et al (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120:275–285

    Article  PubMed  CAS  Google Scholar 

  71. Lee MS, Kwon YT, Li M et al (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364

    Article  PubMed  CAS  Google Scholar 

  72. Nath R, Davis M, Probert AW et al (2000) Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells. Biochem Biophys Res Commun 274:16–21

    Article  PubMed  CAS  Google Scholar 

  73. Chen M, He H, Zhan S et al (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 276:30724–30728

    Article  PubMed  CAS  Google Scholar 

  74. Mandic A, Viktorsson K, Strandberg L et al (2002) Calpain-mediated Bid cleavage and calpain-independent Bak modulation: two separate pathways in cisplatin-induced apoptosis. Mol Cell Biol 22:3003–3013

    Article  PubMed  CAS  Google Scholar 

  75. Bernardi P, Krauskopf A, Basso E et al (2006) The mitochondrial permeability transition from in vitro artifact to disease target. Febs J 273:2077–2099

    Article  PubMed  CAS  Google Scholar 

  76. Scheff SW, Sullivan PG (1999) Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 16:783–792

    Article  PubMed  CAS  Google Scholar 

  77. Sullivan PG, Rabchevsky AG, Hicks RR et al (2000) Dose–response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 101:289–295

    Article  PubMed  CAS  Google Scholar 

  78. Farkas O, Lifshitz J, Povlishock JT (2006) Mechanoporation induced by diffuse traumatic brain injury: an irreversible or reversible response to injury? J Neurosci 26:3130–3140

    Article  PubMed  CAS  Google Scholar 

  79. Baines CP, Kaiser RA, Purcell NH et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  PubMed  CAS  Google Scholar 

  80. Basso E, Fante L, Fowlkes J et al (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558–18561

    Article  PubMed  CAS  Google Scholar 

  81. Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34:232–237

    Article  PubMed  CAS  Google Scholar 

  82. Zamzami N, Larochette N, Kroemer G (2005) Mitochondrial permeability transition in apoptosis and necrosis. Cell Death Differ 12(Suppl 2):1478–1480

    Article  PubMed  CAS  Google Scholar 

  83. Novgorodov SA, Chudakova DA, Wheeler BW et al (2011) Developmentally regulated ceramide synthase 6 increases mitochondrial Ca2+ loading capacity and promotes apoptosis. J Biol Chem 286:4644–4658

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I wish to thank Drs. RamaKrisha Badugu, Chen-Guang Yu, Matthew Garcia, Aashish Joshi, Dingyuan Lou, Zhen Pang, Colin Rogers, Tomoko Sengoku, Yanzhang Li, Ms. Vimala Bondada, Ms. Ranjana Singh, and other lab members for the primary results from our laboratory. The research in the author’s laboratory was supported by funding from the National Institutes of Health and from the Kentucky Spinal Cord and Head Injury Research Trust.

Author information

Authors and Affiliations

  1. Spinal Cord and Brain Injury Research Center and Department of Anatomy and Neurobiology, University of Kentucky, 741 S. Limestone Street, Lexington, KY, 40536-0509, USA

    James W. Geddes

Authors
  1. James W. Geddes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James W. Geddes .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Institute of Cardiovascular Sciences, University of Manitoba, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada

    Naranjan S. Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Geddes, J.W. (2013). Mitochondrial Calpains: Who, What, Where, When and Why?. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9233-7_2

Download citation

Publish with us

Policies and ethics

Search

Navigation