Mitochondrial proteases as emerging pharmacological targets

Current Pharmaceutical Design

Volumn 22, Issue 18, 2016, Pages 2679-2688

  Gibellini, Lara ^a   De Biasi, Sara ^a   Nasi, Milena ^a   Iannone, Anna ^a   Cossarizza, Andrea ^a   Pinti, Marcello ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

CLPP; HTRA2; Inhibitors; LONP1; Mitochondria; Mitochondrial proteases

Indexed keywords

ENDOPEPTIDASE CLP; ENDOPEPTIDASE LA; SERINE PROTEINASE OMI; PEPTIDE HYDROLASE; PROTEIN KINASE INHIBITOR;

ALZHEIMER DISEASE; ARTICLE; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; BLADDER CANCER; COLON CANCER; ESSENTIAL TREMOR; GENE MUTATION; HUMAN; LARGE CELL LYMPHOMA; MELANOMA; MEMBRANE DEPOLARIZATION; MITOCHONDRION; MITOPHAGY; NON SMALL CELL LUNG CANCER; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PARKINSON DISEASE; PRIORITY JOURNAL; PROSTATE CANCER; RESPIRATORY CHAIN; UNFOLDED PROTEIN RESPONSE; ANIMAL; DRUG EFFECTS; ENZYMOLOGY; METABOLISM; PROTEIN UNFOLDING;

ANIMALS; HUMANS; MITOCHONDRIA; PEPTIDE HYDROLASES; PROTEIN KINASE INHIBITORS; PROTEIN UNFOLDING;

EID: 84974722361     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612822666160202130344     Document Type: Article

References (149)

1. Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res 2015.
2. Bohovych I, Chan SS, Khalimonchuk O. Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. Antioxid Redox Signal 2015; 22(12): 977-94.
3. Zhao Q, Wang J, Levichkin IV, et al. A mitochondrial specific stress response in mammalian cells. EMBO J 2002; 21(17): 4411-9.
4. Haynes CM, Petrova K, Benedetti C, et al. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev Cell 2007; 13(4): 467-80.
5. Haynes CM, Yang Y, Blais SP, et al. The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol Cell 2010; 37(4): 529-40.
6. Nargund AM, Pellegrino MW, Fiorese CJ, et al. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 2012; 337(6094): 587-90.
7. Aldridge JE, Horibe T, Hoogenraad NJ. Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS One 2007; 2(9): e874.
8. Horibe T, Hoogenraad NJ. The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS One 2007; 2(9): e835.
9. Tan K, Fujimoto M, Takii R, et al. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat Commun 2015; 6: 6580.
10. Chan DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell 2006; 125(7): 1241-52.
11. Chan DC. Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet 2012; 46: 265-87.
12. Chen H, Detmer SA, Ewald AJ, et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 2003; 160(2): 189-200.
13. Cipolat S, Martins de Brito O, Dal Zilio B, et al. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 2004; 101(45): 15927-32.
14. Ishihara N, Fujita Y, Oka T, et al. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 2006; 25(13): 2966-77.
15. Song Z, Chen H, Fiket M, et al. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 2007; 178(5): 749-55.
16. Delettre C, Griffoin JM, Kaplan J, et al. Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 2001; 109(6): 584-91.
17. Cipolat S, Rudka T, Hartmann D, et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 2006; 126(1): 163-75.
18. Ehses S, Raschke I, Mancuso G, et al. Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 2009; 187(7): 1023-36.
19. Griparic L, Kanazawa T, van der Bliek AM. Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 2007; 178(5): 757-64.
20. Kushnareva YE, Gerencser AA, Bossy B, et al. Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 2013; 20(2): 353-65.
21. Zanna C, Ghelli A, Porcelli AM, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 2008; 131(Pt 2): 352-67.
22. Skulachev VP. Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 2001; 26(1): 23-9.
23. Westermann B. Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta 2012; 1817(10): 1833-8.
24. Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science 2012; 337(6098): 1062-5.
25. Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011; 13(5): 589-98.
26. Rambold AS, Kostelecky B, Elia N, et al. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011; 108(25): 10190-5.
27. Rolland SG, Motori E, Memar N, et al. Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion. Proc Natl Acad Sci USA 2013; 110(32): 2967-76.
28. Tondera D, Grandemange S, Jourdain A, et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 2009; 28(11): 1589-600.
29. Sgarbi G, Matarrese P, Pinti M, et al. Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany NY) 2014; 6(4): 296-310.
30. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67-93.
31. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 2007; 462(2): 245-53.
32. Geisler S, Holmstrom KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12(2): 119-31.
33. Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010; 11(12): 872-84.
34. Jin SM, Lazarou M, Wang C, et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 2010; 191(5): 933-942.
35. Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014; 510(7503): 162-6.
36. Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 2015; 524(7565): 309-14.
37. Narendra D, Tanaka A, Suen DF, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183(5): 795-803.
38. Apostolova N, Gomez-Sucerquia LJ, Gortat A, et al. Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy. Hepatology 2011; 54(3): 1009-19.
39. Gibellini L, De Biasi S, Pinti M, et al. The protease inhibitor atazanavir triggers autophagy and mitophagy in human preadipocytes. AIDS 2012; 26(16): 2017-26.
40. Sentelle RD, Senkal CE, Jiang W, et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol 2012; 8(10): 831-8.
41. Quiros PM, Langer T, Lopez-Otin C. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 2015; 16(6): 345-59.
42. Honbou K, Suzuki NN, Horiuchi M, et al. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J Biol Chem 2003; 278(33): 31380-4.
43. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003; 299(5604): 256-9.
44. Gakh O, Cavadini P, Isaya G. Mitochondrial processing peptidases. Biochim Biophys Acta 2002; 1592(1): 63-77.
45. Jobling RK, Assoum M, Gakh O, et al. PMPCA mutations cause abnormal mitochondrial protein processing in patients with nonprogressive cerebellar ataxia. Brain 2015; 138(Pt 6): 1505-17.
46. Lopez-Otin C, Bond JS. Proteases: multifunctional enzymes in life and disease. J Biol Chem 2008; 283(45): 30433-7.
47. Banfi S, Bassi MT, Andolfi G, et al. Identification and characterization of AFG3L2, a novel paraplegin-related gene. Genomics 1999; 59(1): 51-8.
48. Zeng X, Neupert W, Tzagoloff A. The metalloprotease encoded by ATP23 has a dual function in processing and assembly of subunit 6 of mitochondrial ATPase. Mol Biol Cell 2007; 18(2): 617-26.
49. Corydon TJ, Bross P, Holst HU, et al. A human homologue of Escherichia coli ClpP caseinolytic protease: recombinant expression, intracellular processing and subcellular localization. Biochem J 1998; 331 (Pt 1): 309-16.
50. Gray CW, Ward RV, Karran E, et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 2000; 267(18): 5699-710.
51. Petek E, Windpassinger C, Vincent JB, et al. Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome. Am J Hum Genet 2001; 68(4): 848-58.
52. Smith TS, Southan C, Ellington K, et al. Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain. Genomics 2001; 78(1-2): 12-4.
53. Wang N, Gottesman S, Willingham MC, et al. A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease. Proc Natl Acad Sci USA 1993; 90(23): 11247-51.
54. Serizawa A, Dando PM, Barrett AJ. Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase. J Biol Chem 1995; 270(5): 2092-8.
55. Head B, Griparic L, Amiri M, et al. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 2009; 187(7): 959-66.
56. Sik A, Passer BJ, Koonin EV, et al. Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide. J Biol Chem 2004; 279(15): 15323-9.
57. Mzhavia N, Berman YL, Qian Y, et al. Cloning, expression, and characterization of human metalloprotease 1: a novel member of the pitrilysin family of metalloendoproteases. DNA Cell Biol 1999; 18(5): 369-80.
58. Settasatian C, Whitmore SA, Crawford J, et al. Genomic structure and expression analysis of the spastic paraplegia gene, SPG7. Hum Genet 1999; 105(1-2): 139-44.
59. Nakamura N, Hirose S. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol Biol Cell 2008; 19(5): 1903-11.
60. O'Toole JF, Liu Y, Davis EE, et al. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest 2010; 120(3): 791-802.
61. Coppola M, Pizzigoni A, Banfi S, et al. Identification and characterization of YME1L1, a novel paraplegin-related gene. Genomics 2000; 66(1): 48-54.
62. Cagnoli C, Stevanin G, Brussino A, et al. Missense mutations in the AFG3L2 proteolytic domain account for approximately 1.5% of European autosomal dominant cerebellar ataxias. Hum Mutat 2010; 31(10): 1117-24.
63. Di Bella D, Lazzaro F, Brusco A, et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet 2010; 42(4): 313-21.
64. Edener U, Wollner J, Hehr U, et al. Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation. Eur J Hum Genet 2010; 18(8): 965-8.
65. Gerdes F, Tatsuta T, Langer T. Mitochondrial AAA proteases--towards a molecular understanding of membrane-bound proteolytic machines. Biochim Biophys Acta 2012; 1823(1): 49-55.
66. Almajan ER, Richter R, Paeger L, et al. AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J Clin Invest 2012; 122(11): 4048-58.
67. Pierson TM, Adams D, Bonn F, et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxianeuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet 2011; 7(10): e1002325.
68. Martinelli P, La Mattina V, Bernacchia A, et al. Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. Hum Mol Genet 2009; 18(11): 2001-13.
69. Atorino L, Silvestri L, Koppen M, et al. Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol 2003; 163(4): 777-87.
70. Casari G, De Fusco M, Ciarmatori S, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclearencoded mitochondrial metalloprotease. Cell 1998; 93(6): 973-83.
71. Almontashiri NA, Chen HH, Mailloux RJ, et al. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep 2014; 7(3): 834-47.
72. Pfeffer G, Gorman GS, Griffin H, et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disor dered mitochondrial DNA maintenance. Brain 2014; 137(Pt 5): 1323-36.
73. Shah ZH, Hakkaart GA, Arku B, et al. The human homologue of the yeast mitochondrial AAA metalloprotease Yme1p complements a yeast yme1 disruptant. FEBS Lett 2000; 478(3): 267-70.
74. Stiburek L, Cesnekova J, Kostkova O, et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol Biol Cell 2012; 23(6): 1010-23.
75. Mishra P, Carelli V, Manfredi G, et al. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab 2014; 19(4): 630-41.
76. Kaser M, Kambacheld M, Kisters-Woike B, et al. Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease. J Biol Chem 2003; 278(47): 46414-23.
77. Baker MJ, Lampe PA, Stojanovski D, et al. Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J 2014; 33(6): 578-93.
78. Quiros PM, Ramsay AJ, Sala D, et al. Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J 2012; 31(9): 2117-33.
79. Jiang X, Jiang H, Shen Z, et al. Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. Proc Natl Acad Sci USA 2014; 111(41): 14782-87.
80. Bertelsen B, Melchior L, Jensen LR, et al. Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome. Eur J Hum Genet 2014; 22(11): 1283-9.
81. George SK, Jiao Y, Bishop CE, et al. Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal. Aging Cell 2011; 10(4): 584-94.
82. Patel C, Cooper-Charles L, McMullan DJ, et al. Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome. Eur J Hum Genet 2011; 19(6): 634-9.
83. Kang SG, Dimitrova MN, Ortega J, et al. Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX. J Biol Chem 2005; 280(42): 35424-32.
84. Baker TA, Sauer RT. ClpXP, an ATP-powered unfolding and protein-degradation machine. Biochim Biophys Acta 2012; 1823(1): 15-28.
85. Flynn JM, Neher SB, Kim YI, et al. Proteomic discovery of cellular substrates of the ClpXP protease reveals five classes of ClpXrecognition signals. Mol Cell 2003; 11(3): 671-83.
86. Al-Furoukh N, Ianni A, Nolte H, et al. ClpX stimulates the mitochondrial unfolded protein response (UPR(mt)) in mammalian cells. Biochim Biophys Acta 2015; 1853(10 Pt A): 2580-91.
87. Gispert S, Parganlija D, Klinkenberg M, et al. Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Hum Mol Genet 2013; 22(24): 4871-87.
88. Jenkinson EM, Rehman AU, Walsh T, et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 2013; 92(4): 605-13.
89. Cole A, Wang Z, Coyaud E, et al. Inhibition of the mitochondrial protease ClpP as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 2015; 27(6): 864-76.
90. Zeiler E, Korotkov VS, Lorenz-Baath K, et al. Development and characterization of improved beta-lactone-based anti-virulence drugs targeting ClpP. Bioorg Med Chem 2012; 20(2): 583-91.
91. Suzuki Y, Imai Y, Nakayama H, et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 2001; 8(3): 613-21.
92. Suzuki Y, Takahashi-Niki K, Akagi T, et al. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death Differ 2004; 11(2): 208-16.
93. Hegde R, Srinivasula SM, Zhang Z, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277(1): 432-8.
94. Kuninaka S, Nomura M, Hirota T, et al. The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death. Oncogene 2005; 24(34): 5287-98.
95. Goo HG, Jung MK, Han SS, et al. HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. Biochim Biophys Acta 2013; 1833(8): 1866-75.
96. Li B, Hu Q, Wang H, et al. Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases. Cell Death Differ 2010; 17(11): 1773-84.
97. Moisoi N, Klupsch K, Fedele V, et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brainspecific transcriptional stress response. Cell Death Differ 2009; 16(3): 449-64.
98. Chao JR, Parganas E, Boyd K, et al. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 2008; 452(7183): 98-102.
99. Jones JM, Datta P, Srinivasula SM, et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 2003; 425(6959): 721-7.
100. Martins LM, Morrison A, Klupsch K, et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 2004; 24(22): 9848-62.
101. Kang S, Louboutin JP, Datta P, et al. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ 2013; 20(2): 259-69.
102. Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005; 14(15): 2099-111.
103. Unal Gulsuner H, Gulsuner S, Mercan FN, et al. Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease. Proc Natl Acad Sci USA 2014; 111(51): 18285-90.
104. Martinelli P, Rugarli EI. Emerging roles of mitochondrial proteases in neurodegeneration. Biochim Biophys Acta 2010; 1797(1): 1-10.
105. Bogaerts V, Nuytemans K, Reumers J, et al. Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease. Hum Mutat 2008; 29(6): 832-40.
106. Ross OA, Soto AI, Vilarino-Guell C, et al. Genetic variation of Omi/HtrA2 and Parkinson's disease. Parkinson Relat Disord 2008; 14(7): 539-43.
107. Simon-Sanchez J, Singleton AB. Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet 2008; 17(13): 1988-993.
108. Kawamoto Y, Kobayashi Y, Suzuki Y, et al. Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alphasynucleinopathies. J Neuropathol Exp Neurol 2008; 67(10): 984-93.
109. Behbahani H, Pavlov PF, Wiehager B, et al. Association of Omi/HtrA2 with gamma-secretase in mitochondria. Neurochem Int 2010; 57(6): 668-75.
110. Gupta S, Singh R, Datta P, et al. The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. J Biol Chem 2004; 279(44): 45844-54.
111. Huttunen HJ, Guenette SY, Peach C, et al. HtrA2 regulates betaamyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation. J Biol Chem 2007; 282(38): 28285-95.
112. Park HJ, Kim SS, Seong YM, et al. Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria. J Biol Chem 2006; 281(45): 34277-87.
113. Westerlund M, Behbahani H, Gellhaar S, et al. Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. FASEB J 2011; 25(4): 1345-52.
114. Mao G, Lv L, Liu Y, et al. The expression levels and prognostic value of high temperature required A2 (HtrA2) in NSCLC. Pathol Res Pract 2014; 210(12): 939-43.
115. Miyamoto M, Takano M, Iwaya K, et al. High-temperaturerequired protein A2 as a predictive marker for response to chemotherapy and prognosis in patients with high-grade serous ovarian cancers. Br J Cancer 2015; 112(4): 739-44.
116. Hartkamp J, Carpenter B, Roberts SG. The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi. Mol Cell 2010; 37(2): 159-71.
117. Yamauchi S, Hou YY, Guo AK, et al. p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J Cell Biol 2014; 204(7): 1191-207.
118. Cilenti L, Lee Y, Hess S, et al. Characterization of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. J Biol Chem 2003; 278(13): 11489-94.
119. Cilenti L, Kyriazis GA, Soundarapandian MM, et al. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Am J Physiol Renal Physiol 2005; 288(2): F371-9.
120. Althaus J, Siegelin MD, Dehghani F, et al. The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. Neurochem Int 2007; 50(1): 172-80.
121. Goffredo D, Rigamonti D, Zuccato C, et al. Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease. Pharmacol Res 2005; 52(2): 140-50.
122. Wang N, Maurizi MR, Emmert-Buck L, et al. Synthesis, processing, and localization of human Lon protease. J Biol Chem 1994; 269(46): 29308-13.
123. Gibellini L, Pinti M, Beretti F, et al. Sirtuin 3 interacts with Lon protease and regulates its acetylation status. Mitochondrion 2014; 18: 76-81.
124. Rotanova TV, Melnikov EE, Khalatova AG, et al. Classification of ATP-dependent proteases Lon and comparison of the active sites of their proteolytic domains. Eur J Biochem 2004; 271(23-24): 4865-71.
125. Garcia-Nafria J, Ondrovicova G, Blagova E, et al. Structure of the catalytic domain of the human mitochondrial Lon protease: proposed relation of oligomer formation and activity. Protein Sci 2010; 19(5): 987-99.
126. Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol 2002; 4(9): 674-80.
127. Kita K, Suzuki T, Ochi T. Diphenylarsinic acid promotes degradation of glutaminase C by mitochondrial Lon protease. J Biol Chem 2012; 287(22): 18163-72.
128. Granot Z, Kobiler O, Melamed-Book N, et al. Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors. Mol Endocrinol 2007; 21(9): 2164-77.
129. Tian Q, Li T, Hou W, et al. Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. J Biol Chem 2011; 286(30): 26424-30.
130. Teng H, Wu B, Zhao K, et al. Oxygen-sensitive mitochondrial accumulation of cystathionine beta-synthase mediated by Lon protease. Proc Natl Acad Sci USA 2013; 110(31): 12679-84.
131. Lu B, Lee J, Nie X, et al. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol Cell 2013; 49(1): 121-32.
132. Matsushima Y, Goto Y, Kaguni LS. Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). Proc Natl Acad Sci USA 2010; 107(43): 18410-5.
133. Jin SM, Youle RJ. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkinmediated mitophagy of polarized mitochondria. Autophagy 2013; 9(11): 1750-7.
134. Bahat A, Perlberg S, Melamed-Book N, et al. Transcriptional activation of LON Gene by a new form of mitochondrial stress: A role for the nuclear respiratory factor 2 in StAR overload response (SOR). Mol Cell Endocrinol 2015; 408: 62-72.
135. Ngo JK, Davies KJ. Mitochondrial Lon protease is a human stress protein. Free Radic Biol Med 2009; 46(8): 1042-8.
136. Pinti M, Gibellini L, De Biasi S, et al. Functional characterization of the promoter of the human Lon protease gene. Mitochondrion 2011; 11(1): 200-6.
137. Pinti M, Gibellini L, Guaraldi G, et al. Upregulation of nuclearencoded mitochondrial LON protease in HAART-treated HIVpositive patients with lipodystrophy: implications for the pathogenesis of the disease. AIDS 2010; 24(6): 841-50.
138. Quiros PM, Espanol Y, Acin-Perez R, et al. ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep 2014; 8(2): 542-56.
139. Dikoglu E, Alfaiz A, Gorna M, et al. Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. Am J Med Genet A 2015; 167(7): 1501-9.
140. Strauss KA, Jinks RN, Puffenberger EG, et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet 2015; 96(1): 121-35.
141. Bernstein SH, Venkatesh S, Li M, et al. The mitochondrial ATPdependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 2012; 119(14): 3321-9.
142. Gibellini L, Pinti M, Boraldi F, et al. Silencing of mitochondrial Lon protease deeply impairs mitochondrial proteome and function in colon cancer cells. FASEB J 2014; 28(12): 5122-35.
143. Liu Y, Lan L, Huang K, et al. Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer. Oncotarget 2014; 5(22): 11209-24.
144. Cheng CW, Kuo CY, Fan CC, et al. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis 2013; 4: e681.
145. Pinti M, Gibellini L, Liu Y, et al. Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell Mol Life Sci 2015.
146. Bayot A, Basse N, Lee I, et al. Towards the control of intracellular protein turnover: mitochondrial Lon protease inhibitors versus proteasome inhibitors. Biochimie 2008; 90(2): 260-9.
147. Wang HM, Cheng KC, Lin CJ, et al. Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints. Cancer Sci 2010; 101(12): 2612-20.
148. Gibellini L, Pinti M, Bartolomeo R, et al. Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells. Oncotarget 2015; 6(28): 25466-83.
149. Fishovitz J, Li M, Frase H, et al. Active-site-directed chemical tools for profiling mitochondrial Lon protease. ACS Chem Biol 2011; 6(8): 781-8.