The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age1,2. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages3. Here we have identified the mnd2 mutation as the missense mutation Ser276Cys in the protease domain of the nuclear-encoded mitochondrial serine protease Omi (also known as HtrA2 or Prss25). Protease activity of Omi is greatly reduced in tissues of mnd2 mice but is restored in mice rescued by a bacterial artificial chromosome transgene containing the wild-type Omi gene. Deletion of the PDZ domain partially restores protease activity to the inactive recombinant Omi protein carrying the Ser276Cys mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. The neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease.
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Jones, J. M. et al. mnd2: a new mouse model of inherited motor neuron disease. Genomics 16, 669–677 (1993)
Weber, J. S. et al. High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6. Genomics 54, 107–115 (1998)
Rathke-Hartlieb, S. et al. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Exp. Neurol. 175, 87–97 (2002)
Jang, W. et al. Comparative sequence of human and mouse BAC clones from the mnd2 region of chromosome 2p13. Genome Res. 9, 53–61 (1999)
Jang, W., Weber, J. S., Bashir, R., Bushby, K. & Meisler, M. H. Aup1, a novel gene on mouse chromosome 6 and human chromosome 2p13. Genomics 36, 366–368 (1996)
Jang, W., Weber, J. S., Harkins, E. B. & Meisler, M. H. Localization of the rhotekin gene RTKN on the physical maps of mouse chromosome 6 and human chromosome 2p13 and exclusion as a candidate for mnd2 and LGMD2B. Genomics 40, 506–507 (1997)
Jang, W., Weber, J. S., Tokito, M. K., Holzbaur, E. L. & Meisler, M. H. Mouse p150Glued (dynactin 1) cDNA sequence and evaluation as a candidate for the neuromuscular disease mutation mnd2. Biochem. Biophys. Res. Commun. 231, 344–347 (1997)
Ji, W. et al. DQX1, an RNA-dependent ATPase homolog with a novel DEAQ box: expression pattern and genomic sequence comparison of the human and mouse genes. Mamm. Genome 12, 456–461 (2001)
Li, W. et al. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nature Struct. Biol. 9, 436–441 (2002)
Hegde, R. et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 277, 432–438 (2002)
Suzuki, Y. et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8, 613–621 (2001)
Verhagen, A. M. et al. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 277, 445–454 (2002)
Martins, L. M. et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J. Biol. Chem. 277, 439–444 (2002)
van Loo, G. et al. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ. 9, 20–26 (2002)
Clausen, T., Southan, C. & Ehrmann, M. The HtrA family of proteases: implications for protein composition and cell fate. Mol. Cell 10, 443–455 (2002)
Maurizi, M. R. Love it or cleave it: tough choices in protein quality control. Nature Struct. Biol. 9, 410–412 (2002)
Srinivasula, S. M. et al. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. J. Biol. Chem. 278, 31469–31472 (2003)
Yang, Q. H., Church-Hajduk, R., Ren, J., Newton, M. L. & Du, C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 17, 1487–1496 (2003)
Brustovetsky, N. et al. Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J. Neurosci. 23, 4858–4867 (2003)
Szalai, G., Krishnamurthy, R. & Hajnoczky, G. Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J. 18, 6349–6361 (1999)
Reed, J. C. Cytochrome c: can't live with it—can't live without it. Cell 91, 559–562 (1997)
Joza, N. et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410, 549–554 (2001)
Klein, J. A. et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 419, 367–374 (2002)
Walsh, N. P., Alba, B. M., Bose, B., Gross, C. A. & Sauer, R. T. OMP peptide signals initiate the envelope-stress response by activating DegS protease via relief of inhibition mediated by its PDZ domain. Cell 113, 61–71 (2003)
Leist, M., Single, B., Castoldi, A. F., Kuhnle, S. & Nicotera, P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185, 1481–1486 (1997)
Susin, S. A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999)
Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956 (2003)
Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998)
Van Dyck, L. & Langer, T. ATP-dependent proteases controlling mitochondrial function in the yeast Saccharomyces cerevisiae. Cell. Mol. Life Sci. 56, 825–842 (1999)
This work was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association. S.M.S. is a Kimmel scholar. W.J. acknowledges support from the Hearing and Chemical Senses Training Program of the University of Michigan. We thank J. Zhang for help in preparation of MEFs and A. Zervos for the mouse Omi cDNA. We also thank M. Farrer and T. Gasser for the PARK3 DNA samples.
The authors declare that they have no competing financial interests.Authors' contributions J.M.J., P.D., S.M.S. and W.J. share equal first authorship and E.S.A. and M.H.M. share equal senior authorship.
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Jones, J., Datta, P., Srinivasula, S. et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425, 721–727 (2003). https://doi.org/10.1038/nature02052
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