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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    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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    • "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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    ABSTRACT: Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration.
    The EMBO Journal 02/2012; 31(6):1336-49. DOI:10.1038/emboj.2012.38 · 10.75 Impact Factor
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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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    ABSTRACT: Cell homeostasis results from the balance between cell capability to adapt or succumb to environmental stress. Mitochondria, in addition to supplying cellular energy, are involved in a range of processes deciding about cellular life or death. The crucial role of mitochondria in cell death is well recognized. Mitochondrial dysfunction has been associated with the death process and the onset of numerous diseases. Yet, mitochondrial involvement in cellular adaptation to stress is still largely unexplored. Strong interest exists in pharmacological manipulation of mitochondrial metabolism and signaling. The yeast Saccharomyces cerevisiae has proven a valuable model organism in which several intracellular processes have been characterized in great detail, including the retrograde response to mitochondrial dysfunction and, more recently, programmed cell death. In this paper we review experimental evidences of mitochondrial involvement in cytoprotection and propose yeast as a model system to investigate the role of mitochondria in the cross-talk between prosurvival and prodeath pathways.
    The Scientific World Journal 02/2012; 2012:912147. DOI:10.1100/2012/912147 · 1.73 Impact Factor
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