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Jones, J. M. 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: 42.35). 11/2003; 425(6959):721-7. DOI: 10.1038/nature02052
Source: PubMed

ABSTRACT 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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Available from: Gyorgy Hajnoczky, Aug 20, 2015
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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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    • "The mitochondrial peptidase HTRA2/OMI, which is localized to the mitochondrial intermembrane space and homologous to the bacterial HtrA stress responsive genes, DegP and DegS (Vande Walle et al, 2008; Clausen et al, 2011), plays a critical role in protecting neurons against degeneration and has been associated with PD. Both a spontaneous mutation and a targeted deletion in the murine Htra2 gene were shown to cause a progressive neurodegenerative phenotype, characterized by abnormal gait, ataxia, repetitive movements and akinesia, owing to loss of neurons in the striatum (Jones et al, 2003; Martins et al, 2004). While its role in neuronal survival is well established, the implication of HTRA2 in the pathogenesis of PD remains controversial. "
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    • "Activation of caspases is shown to be necessary for processes such as terminal differentiation, activation, proliferation, and cytoprotection [25]. Caspase-independent death effectors, such as AIF and Omi/HtrA2, are released from the mitochondrial intermembrane space upon apoptosis induction, but these proteins also have important functions in cellular redox metabolism and/or mitochondrial biogenesis [26] [27] [28]. "
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