Decrease of ATP by mitochondrial m-calpain inhibitory peptide in the rat retinas.

Activations of mitochondrial calpains cause apoptosis-inducing factor-dependent apoptosis of retinal photoreceptor cells in the Royal College of Surgeons (RCS) rat, an animal model of retinitis pigmentosa. In the present study, we attempted to develop specific inhibitors of mitochondrial calpains that would prevent the retinal degeneration. We examined the inhibitory potency of 20-mer peptides of the m-calpain for mitochondrial calpains activity, determined the inhibitory regions, and conjugated the cell-penetrating peptides (CPP). The cytotoxicity and delivery of the peptide was evaluated using mouse photoreceptor-derived 661W cells. After intravitreal injection of the peptide in RCS rats, we examined the peptide delivery to the retina, photoreceptor cell death numbers, responses of the electroretinogram (ERG), concentrations of intracellular ATP, and changes of retinal morphology. Results showed that one of the peptides inhibited the activity of the mitochondrial m-calpain. The HIV-1 tat-conjugated m-calpain peptide, HIV-Nm, could preserve the inhibitory potency of the mitochondrial m-calpain, and penetrate into the 661W cells. While intravitreal injection of HIV-Nm made it possible to deliver to the retina, it did not prevent photoreceptor cell death. Furthermore, it caused the ERG attenuation and the decrease in the intracellular ATP only a day after the injection. Although HIV-Nm did not cause histological change of the retina after 1 or 2 days of the administration, the morphological abnormality of the retina was observed after 3-14 days. Our results demonstrated that HIV-Nm failed to prevent the photoreceptor cell death, but rather caused the attenuation of ERG response and the decrease of ATP.

[1]  H. Itoh,et al.  Cisplatin Binding and Inactivation of Mitochondrial Glutamate Oxaloacetate Transaminase in Cisplatin-Induced Rat Nephrotoxicity , 2013, Bioscience, biotechnology, and biochemistry.

[2]  H. Tomita,et al.  Inhibitory Peptide of Mitochondrial μ-Calpain Protects against Photoreceptor Degeneration in Rhodopsin Transgenic S334ter and P23H Rats , 2013, PloS one.

[3]  H. Tomita,et al.  Intravitreal injection or topical eye-drop application of a μ-calpain C2L domain peptide protects against photoreceptor cell death in Royal College of Surgeons' rats, a model of retinitis pigmentosa. , 2012, Biochimica et biophysica acta.

[4]  R. Schnellmann,et al.  Loss of calpain 10 causes mitochondrial dysfunction during chronic hyperglycemia. , 2012, Archives of biochemistry and biophysics.

[5]  T. Nakazawa,et al.  Critical role of calpain in axonal damage‐induced retinal ganglion cell death , 2012, Journal of neuroscience research.

[6]  E. Zrenner,et al.  Calpain and PARP Activation during Photoreceptor Cell Death in P23H and S334ter Rhodopsin Mutant Rats , 2011, PloS one.

[7]  H. Sorimachi,et al.  Impact of genetic insights into calpain biology. , 2011, Journal of biochemistry.

[8]  N. Cuenca,et al.  Rotenone induces degeneration of photoreceptors and impairs the dopaminergic system in the rat retina , 2011, Neurobiology of Disease.

[9]  T. Yamashita,et al.  Ca²+-induced release of mitochondrial m-calpain from outer membrane with binding of calpain small subunit and Grp75. , 2011, Archives of biochemistry and biophysics.

[10]  V. Shestopalov,et al.  Liposome-delivered ATP effectively protects the retina against ischemia-reperfusion injury , 2010, Molecular vision.

[11]  L. Kowalczuk,et al.  Protein delivery for retinal diseases: From basic considerations to clinical applications , 2010, Progress in Retinal and Eye Research.

[12]  T. van Veen,et al.  Photoreceptor rescue and toxicity induced by different calpain inhibitors , 2010, Journal of neurochemistry.

[13]  Tomomi Metoki,et al.  Activation of mitochondrial calpain and release of apoptosis-inducing factor from mitochondria in RCS rat retinal degeneration. , 2010, Experimental eye research.

[14]  Danyi Wang,et al.  Mechanisms of retinal ganglion cell injury and defense in glaucoma. , 2010, Experimental eye research.

[15]  C. Grosskreutz,et al.  Calpain activation in experimental glaucoma. , 2010, Investigative ophthalmology & visual science.

[16]  B. Zhivotovsky,et al.  Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). , 2010, Biochemical and biophysical research communications.

[17]  S. Chakraborti,et al.  Mitochondrial calpain system: an overview. , 2010, Archives of biochemistry and biophysics.

[18]  T. Yamashita,et al.  Mitochondrial m-calpain plays a role in the release of truncated apoptosis-inducing factor from the mitochondria. , 2009, Biochimica et biophysica acta.

[19]  K. Nakagawa,et al.  Inhibition of nuclear translocation of apoptosis-inducing factor is an essential mechanism of the neuroprotective activity of pigment epithelium-derived factor in a rat model of retinal degeneration. , 2008, The American journal of pathology.

[20]  T. Yamashita,et al.  ERp57-associated mitochondrial μ-calpain truncates apoptosis-inducing factor. , 2008, Biochimica et biophysica acta.

[21]  J. Geddes,et al.  N Terminus of Calpain 1 Is a Mitochondrial Targeting Sequence* , 2008, Journal of Biological Chemistry.

[22]  H. Tomita,et al.  Characteristics of mitochondrial calpains. , 2007, Journal of biochemistry.

[23]  R. Schnellmann,et al.  Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. , 2006, American journal of physiology. Cell physiology.

[24]  W. Kwong,et al.  Postnatal Developmental Changes of Vitreous and Lens Volumes in Sprague-Dawley Rats , 2006, Neuroembryology and Aging.

[25]  M. Ueffing,et al.  Calpain is activated in degenerating photoreceptors in the rd1 mouse , 2006, Journal of neurochemistry.

[26]  J. Geddes,et al.  Mitochondrial localization of μ-calpain , 2005 .

[27]  T. Cotter,et al.  Activation of multiple pathways during photoreceptor apoptosis in the rd mouse. , 2005, Investigative ophthalmology & visual science.

[28]  D. Nicholls,et al.  Calpain I Induces Cleavage and Release of Apoptosis-inducing Factor from Isolated Mitochondria* , 2005, Journal of Biological Chemistry.

[29]  D. N. Deaton,et al.  Ketoamide-based inhibitors of cysteine protease, cathepsin K: P3 modifications. , 2004, Journal of Medicinal Chemistry.

[30]  D. E. Goll,et al.  The calpain system. , 2003, Physiological reviews.

[31]  S. Futaki,et al.  Possible Existence of Common Internalization Mechanisms among Arginine-rich Peptides* , 2002, The Journal of Biological Chemistry.

[32]  M. Lazdunski,et al.  ATP-sensitive potassium channels (KATP) in retina: a key role for delayed ischemic tolerance , 2001, Brain Research.

[33]  M. Lavail,et al.  Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. , 2000, Human molecular genetics.

[34]  C. Crews,et al.  Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Barrett,et al.  Inhibition of Mammalian Legumain by Some Cystatins Is Due to a Novel Second Reactive Site* , 1999, The Journal of Biological Chemistry.

[36]  T. Torgerson,et al.  Inhibition of Nuclear Translocation of Transcription Factor NF-κB by a Synthetic Peptide Containing a Cell Membrane-permeable Motif and Nuclear Localization Sequence (*) , 1995, The Journal of Biological Chemistry.

[37]  J Barsoum,et al.  Tat-mediated delivery of heterologous proteins into cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Sorimachi,et al.  Calpains: an elaborate proteolytic system. , 2012, Biochimica et biophysica acta.

[39]  P. Humphries,et al.  Calpain and photoreceptor apoptosis. , 2012, Advances in experimental medicine and biology.

[40]  村上 祐介.  Inhibition of nuclear translocation of apoptosis-inducing factor is an essential mechanism of the neuroprotective activity of pigment epithelium-derived factor in a rat model of retinal degeneration , 2009 .