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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    ABSTRACT: The cell has an intricate quality control system to protect its mitochondria from oxidative stress. This surveillance system is multi-tiered and comprises molecules that are present inside the mitochondria, in the cytosol, and in other organelles like the nucleus and endoplasmic reticulum. These molecules cross talk with each other and protect the mitochondria from oxidative stress. Oxidative stress is a fundamental part of early disease pathogenesis of neurodegenerative diseases. These disorders also damage the cellular quality control machinery that protects the cell against oxidative stress. This exacerbates the oxidative damage and causes extensive neuronal cell death that is characteristic of neurodegeneration.
    The Scientific World Journal 10/2013; 2013(14):180759. DOI:10.1155/2013/180759 · 1.73 Impact Factor
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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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    ABSTRACT: Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). Cyclophilin D (CypD) and reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aβ) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aβ neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction and Neurodegenerative Diseases.
    Biochimica et Biophysica Acta 09/2013; 1842(8). DOI:10.1016/j.bbadis.2013.09.003 · 4.66 Impact Factor
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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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    ABSTRACT: In both flies and mammals, almost one-third of the newly emerging male germ cells are spontaneously eliminated before entering meiosis. Here, we show that in Drosophila, germ cell death (GCD) involves the initiator caspase Dronc independently of the apoptosome and the main executioner caspases. Electron microscopy of dying germ cells revealed mixed morphologies of apoptosis and necrosis. We further show that the lysosomes and their catabolic enzymes, but not macroautophagy, are involved in the execution of GCD. We then identified, in a screen, the Parkinson's disease-associated mitochondrial protease, HtrA2/Omi, as an important mediator of GCD, acting mainly through its catalytic activity rather than by antagonizing inhibitor of apoptosis proteins. Concomitantly, other mitochondrial-associated factors were also implicated in GCD, including Pink1 (but not Parkin), the Bcl-2-related proteins, and endonuclease G, which establish the mitochondria as central mediators of GCD. These findings uncover an alternative developmental cell death pathway in metazoans.
    Developmental Cell 03/2013; 25(1). DOI:10.1016/j.devcel.2013.02.002 · 9.71 Impact Factor
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