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Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice


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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Figure 1: Genetic and physical map of the mnd2 region.
Figure 2: Ser276Cys mutation in Omi.
Figure 3: Effect of the Ser276Cys mutation on the protease activity of Omi.
Figure 4: Structural determinants of Omi activity.
Figure 5: Sensitivity of mnd2 MEFs to stress-induced cell death.
Figure 6: Ca2+ pulsing-induced mitochondrial membrane permeabilization in mnd2 MEFs.


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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.

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Correspondence to Miriam H. Meisler or Emad S. Alnemri.

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Competing interests

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).

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