Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics

References

• Glynn SE. multifunctional Mitochondrial AAA proteases. Front Mol Biosci. 2017;4:34. doi: 10.3389/fmolb.2017.00034
   PubMed Web of Science ®Google Scholar
• Quirós Pedro M, Español Y, Acín-Pérez R, et al. ATP-Dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep. 2014;8(2):542–556. doi: 10.1016/j.celrep.2014.06.018
   PubMed Web of Science ®Google Scholar
• Gibellini L, De Gaetano A, Mandrioli M, et al. The biology of Lonp1: more than a mitochondrial protease. Int Rev Cell Mol Biol. 2020;354:1–61.
   PubMed Web of Science ®Google Scholar
• 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 Sep;21(9):2164–77.
   PubMedGoogle Scholar
• 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 Jul 29;286(30):26424–30. doi: 10.1074/jbc.M110.215772
   PubMed Web of Science ®Google Scholar
• 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 Jan 10;49(1):121–32. doi: 10.1016/j.molcel.2012.10.023
   PubMed Web of Science ®Google Scholar
• Shin CS, Meng S, Garbis SD, et al. LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding. Nat Commun. 2021 Jan 11;12(1):265. doi: 10.1038/s41467-020-20597-z
   PubMed Web of Science ®Google Scholar
• Bezawork-Geleta A, Brodie EJ, Dougan DA, et al. LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins. Sci Rep. 2015 Dec 02;5(1):17397.
   PubMedGoogle Scholar
• Hori O, Ichinoda F, Tamatani T, et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Bio. 2002 Jun 24;157(7):1151–60. doi: 10.1083/jcb.200108103
   PubMed Web of Science ®Google Scholar
• Crewe C, Schafer C, Lee I, et al. Regulation of pyruvate dehydrogenase kinase 4 in the heart through degradation by the lon protease in response to mitochondrial substrate availability. J Biol Chem. 2017 Jan 6;292(1):305–312. doi: 10.1074/jbc.M116.754127
   PubMed Web of Science ®Google Scholar
• Nimmo GAM, Venkatesh S, Pandey AK, et al. Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. Hum Mol Genet. 2019 Jan 15;28(2):290–306. doi: 10.1093/hmg/ddy351
   PubMed Web of Science ®Google Scholar
• Haynes CM, Hekimi S, Driscoll M. Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in caenorhabditis elegans. Genetics. 2022 Nov 30;222(4). doi: 10.1093/genetics/iyac160
   PubMed Web of Science ®Google Scholar
• Lu B, Yadav S, Shah PG, et al. Roles for the human ATP-dependent Lon protease in mitochondrial DNA maintenance. J Biol Chem. 2007 Jun 15;282(24):17363–74. doi: 10.1074/jbc.M611540200
   PubMed Web of Science ®Google Scholar
• Liu T, Lu B, Lee I, et al. DNA and RNA binding by the mitochondrial lon protease is regulated by nucleotide and protein substrate. J Biol Chem. 2004 Apr 2;279(14):13902–10. doi: 10.1074/jbc.M309642200
   PubMed Web of Science ®Google Scholar
• Yang Q, Liu P, Anderson NS, et al. LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria. Nat Cell Biol. 2022 Feb;24(2):181–193.
   PubMed Web of Science ®Google Scholar
• 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 Jan 8;96(1):121–35. doi: 10.1016/j.ajhg.2014.12.003
   PubMed Web of Science ®Google Scholar
• Dikoglu E, Alfaiz A, Gorna M, et al. Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. Am J Med Genet A. 2015 Jul;167(7):1501–9.
   PubMed Web of Science ®Google Scholar
• Fukuda R, Zhang H, Kim JW, et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007 Apr 6;129(1):111–22. doi: 10.1016/j.cell.2007.01.047
   PubMed Web of Science ®Google Scholar
• Pryde KR, Taanman JW, Schapira AH. A LON-ClpP proteolytic axis degrades complex i to extinguish ros production in depolarized mitochondria. Cell Rep. 2016 Dec 6;17(10):2522–2531.
   PubMed Web of Science ®Google Scholar
• Vaseva AV, Marchenko ND, Ji K, et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis [research support, N.I.H., extramural]. Cell. 2012 Jun 22;149(7):1536–48. doi: 10.1016/j.cell.2012.05.014
   PubMed Web of Science ®Google Scholar
• Sung YJ, Kao TY, Kuo CL, et al. Mitochondrial lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity. Cell Death Dis. 2018 Jun 13;9(6):697. doi: 10.1038/s41419-018-0730-7
   PubMedGoogle Scholar
• Pellegrino MW, Nargund AM, Haynes CM. Signaling the mitochondrial unfolded protein response. Biochim Biophys Acta. 2013 Feb;1833(2):410–6. doi: 10.1016/j.bbamcr.2012.02.019
   PubMed Web of Science ®Google Scholar
• Tian X, Zhang S, Zhou L, et al. Targeting the integrated stress response in cancer therapy. Front Pharmacol. 2021;12:747837. doi: 10.3389/fphar.2021.747837
   PubMed Web of Science ®Google Scholar
• Bernstein SH, Venkatesh S, Li M, et al. The mitochondrial ATP-dependent lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood. 2012;119(14):3321–3329. doi: 10.1182/blood-2011-02-340075
   PubMed Web of Science ®Google Scholar
• Goto M, Miwa H, Suganuma K, et al. Adaptation of leukemia cells to hypoxic condition through switching the energy metabolism or avoiding the oxidative stress. BMC Cancer. 2014 Feb 10;14(1):76. doi: 10.1186/1471-2407-14-76
   PubMedGoogle Scholar
• Lee YG, Kim HW, Nam Y, et al. LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival. Oncogenesis. 2021 Feb 26;10(2):18. doi: 10.1038/s41389-021-00306-1
   PubMed Web of Science ®Google Scholar
• Ghosh JC, Seo JH, Agarwal E, et al. Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits. Oncogene. 2019 Oct;38(43):6926–6939.
   PubMed Web of Science ®Google Scholar
• Uhlén M, Björling E, Agaton C, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol & Cell Proteomics. 2005 Dec 01;4(12):1920–1932. doi: 10.1074/mcp.M500279-MCP200
   PubMed Web of Science ®Google Scholar
• The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/21/23. [Internet]. 2023
   Google Scholar
• LonP1 transcriptomics - these data here are in whole or part based upon data generated by the TCGA research network [Internet]. 2023. Available from: https://www.cancer.gov/tcga
   Google Scholar
• Zanini G, Selleri V, De Gaetano A, et al. Differential expression of Lonp1 isoforms in cancer cells. Cells. 2022;11(23):3940. doi: 10.3390/cells11233940
   PubMed Web of Science ®Google Scholar
• Park JE, Miller Z, Jun Y, et al. Next-generation proteasome inhibitors for cancer therapy. Transl Res. 2018 Aug;198:1–16.
   PubMed Web of Science ®Google Scholar
• Frase H, Hudak J, Lee I. Identification of the proteasome inhibitor MG262 as a potent ATP-dependent inhibitor of the Salmonella enterica serovar typhimurium Lon protease. Biochemistry. 2006 Jul 01;45(27):8264–8274.
   PubMed Web of Science ®Google Scholar
• Lee J, Pandey AK, Venkatesh S, et al. Inhibition of mitochondrial LonP1 protease by allosteric blockade of ATP binding and hydrolysis via CDDO and its derivatives. J Biol Chem. 2022 Mar 01;298(3):101719. doi: 10.1016/j.jbc.2022.101719
   PubMed Web of Science ®Google Scholar
• Kingsley LJ, He X, McNeill M, et al. Structure-based design of selective LONP1 inhibitors for probing in vitro biology. J Med Chem. 2021 Apr 22;64(8):4857–4869. doi: 10.1021/acs.jmedchem.0c02152
   PubMed Web of Science ®Google Scholar
• Bayot A, Basse N, Lee I, et al. Towards the control of intracellular protein turnover: mitochondrial lon protease inhibitors versus proteasome inhibitors. Biochimie. 2008 Feb 01;90(2):260–269. doi: 10.1016/j.biochi.2007.10.010
   PubMed Web of Science ®Google Scholar
• 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 Dec;101(12):2612–2620.
   PubMed Web of Science ®Google Scholar
• Shin M, Watson ER, Song AS, et al. Structures of the human LONP1 protease reveal regulatory steps involved in protease activation. Nat Commun. 2021 May 28;12(1):3239. doi: 10.1038/s41467-021-23495-0
   PubMed Web of Science ®Google Scholar
• Maneix L, Sweeney MA, Lee S, et al. The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma. Cancers (Basel). 2021 Feb 17;13(4):843. doi: 10.3390/cancers13040843
   PubMed Web of Science ®Google Scholar
• Rep M, van Dijl JM, Suda K, et al. Promotion of mitochondrial membrane complex assembly by a proteolytically inactive yeast lon. Science. 1996 Oct 4;274(5284):103–6. doi: 10.1126/science.274.5284.103
   PubMed Web of Science ®Google Scholar
• Lee I, Berdis AJ, Suzuki CK. Recent developments in the mechanistic enzymology of the ATP-dependent lon protease from Escherichia coli: highlights from kinetic studies. Mol Biosyst. 2006 Oct;2(10):477–83. doi: 10.1039/b609936j
   PubMedGoogle Scholar
• Samudio I, Konopleva M, Pelicano H, et al. A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis. Mol Pharmacol. 2006 Apr;69(4):1182–93.
   PubMed Web of Science ®Google Scholar
• Cleasby A, Yon J, Day PJ, et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One. 2014;9(6):e98896. doi: 10.1371/journal.pone.0098896
   PubMed Web of Science ®Google Scholar
• Ahmad R, Raina D, Meyer C, et al. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on cys-179. J Biol Chem. 2006 Nov 24;281(47):35764–35769. doi: 10.1074/jbc.M607160200
   PubMed Web of Science ®Google Scholar
• Ahmad R, Raina D, Meyer C, et al. Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)–>signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res. 2008 Apr 15;68(8):2920–2926.
   PubMed Web of Science ®Google Scholar
• Nouri K, Feng Y, Schimmer AD. Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy. Cell Death Dis. 2020 Oct 9;11(10):841.
   PubMed Web of Science ®Google Scholar