Jones JM, Datta P, Srinivasula SM, Ji W, Gupta S, Zhang Z et al.. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425: 721-727

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0618, USA.
Nature (Impact Factor: 41.46). 11/2003; 425(6959):721-7. DOI: 10.1038/nature02052
Source: PubMed


The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages. 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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    • "Once in the cytosol, it antagonises inhibitors of apoptosis (IAPs), as a result, caspases are activated which result in apoptotic cell death [31]. A missense mutation in the protease domain of HtrA2 (mnd2 mutation) can cause neuromuscular disorder with striatal neuron degeneration [32]. HtrA2 has been found to interact and process amyloid precursor protein (APP) in mouse brains and in cultured cells without any apoptotic stimuli [33]. "
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    • "The CypD-dependent mPTP might also be involved in other diseases. Mitochondria isolated from the livers of neuromuscular disorder of mnd2 mutant mice with mutation of the omi gene are more susceptible to the mPTP [74]. MND2 mice succumb to motor neuron disease [75], which might be caused by mPTP formation occurring at a lower threshold in neuronal mitochondria. "
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    • "Indeed, as opposed to the compelling evidence for the importance of the Reaperfamily proteins in the induction of most if not all developmental and stress-induced cell death in Drosophila (Fuchs and Steller, 2011), HtrA2/Omi has been shown to be dispensable for apoptosis in flies (Yun et al., 2008; Tain et al., 2009). Likewise, htrA2/omi knockout/mutant mice displayed no apoptosisrelated phenotypes (Jones et al., 2003). It is also interesting to note that the IBM of HtrA2/Omi is not conserved in all mammalian homologs (Li et al., 2002). "
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