Late-Onset Corticohippocampal Neurodepletion Attributable to Catastrophic Failure of Oxidative Phosphorylation in MILON Mice

Departments of Medical Nutrition and Biosciences, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2001; 21(20):8082-90.
Source: PubMed


We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At approximately 5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

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Available from: Mats I Ekstrand, Apr 07, 2014
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    • "Recently, a growing body of evidence indicates that mitochondrial fusion and fission have important roles in establishing, maintaining, and remodeling mitochondrial function. The abnormalities in mitochondrial dynamics are associated with neurodegenerative diseases, cardiovascular disorders, and diabetes mellitus [29], [30], [31]. In the present study, GCDCA stimulated morphological changes in the mitochondria of L02 cells from the characteristic long shape to a round and short shape, which may suggest that defects in organelle fusion and fission are important in extrahepatic cholestasis. "
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    ABSTRACT: Mitochondrial impairment is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling and is involved in the development of numerous mitochondrial-related diseases; however, a functional role for Mfn2 in chronic liver cholestasis which is characterized by increased levels of toxic bile acids remain unknown. Therefore, the aims of this study were to evaluate the expression levels of Mfn2 in liver samples from patients with extrahepatic cholestasis and to investigate the role Mfn2 during bile acid induced injury in vitro. Endogenous Mfn2 expression decreased in patients with extrahepatic cholestasis. Glycochenodeoxycholic acid (GCDCA) is the main toxic component of bile acid in patients with extrahepatic cholestasis. In human normal hepatocyte cells (L02), Mfn2 plays an important role in GCDCA-induced mitochondrial damage and changes in mitochondrial morphology. In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions. Moreover, the overexpression of Mfn2 effectively attenuated mitochondrial fragmentation and reversed the mitochondrial damage observed in GCDCA-treated L02 cells. Notably, a truncated Mfn2 mutant that lacked the normal C-terminal domain lost the capacity to induce mitochondrial fusion. Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA. Taken together, these findings indicate that the loss of Mfn2 may play a crucial role the pathogenesis of the liver damage that is observed in patients with extrahepatic cholestasis. The findings also indicate that Mfn2 may directly regulate mitochondrial metabolism independently of its primary fusion function. Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis.
    PLoS ONE 06/2013; 8(6):e65455. DOI:10.1371/journal.pone.0065455 · 3.23 Impact Factor
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    • "To determine the functional effect of deleting Tfam in the ENS, we next assessed mtDNA copy number in YFP-positive enteric neurons and glia from 7 week old YFP/Tfam-ENSKO and YFP/control mice. Tfam has an essential role in the maintenance and replication of mtDNA [19], [20] and previous reports have described severe mtDNA depletion following tissue-specific excision of Tfam from a cell of interest [19], [21]–[25]. Consistent with this, we found an 80% reduction in total mtDNA content in enteric neurons and glia isolated from different regions throughout the gut of YFP/Tfam-ENSKO mice (Fig. 1d). "
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    ABSTRACT: Mitochondrial dysfunction is a central mediator of disease progression in diverse neurodegenerative diseases that often present with prominent gastrointestinal abnormalities. Gastrointestinal dysfunction in these disorders is related, at least in part, to defects in the enteric nervous system (ENS). The role of mitochondrial deficits in ENS neurodegeneration and their relative contribution to gastrointestinal dysfunction, however, are unclear. To better understand how mitochondrial abnormalities in the ENS influence enteric neurodegeneration and affect intestinal function, we generated mice (Tfam-ENSKOs) with impaired mitochondrial metabolism in enteric neurons and glia through the targeted deletion of the mitochondrial transcription factor A gene (Tfam). Tfam-ENSKO mice were initially viable but, at an early age, they developed severe gastrointestinal motility problems characterized by intestinal pseudo-obstruction resulting in premature death. This gastrointestinal dysfunction was caused by extensive, progressive neurodegeneration of the ENS involving both neurons and glia. Interestingly, mitochondrial defects differentially affected specific subpopulations of enteric neurons and regions of the gastrointestinal tract. Mitochondrial deficiency-related neuronal and glial loss was most prominent in the proximal small intestine, but the first affected neurons, nitrergic inhibitory neurons, had the greatest losses in the distal small intestine. This regional and subtype-specific variability in susceptibility to mitochondrial defects resulted in an imbalance of inhibitory and excitatory neurons that likely accounts for the observed phenotype in Tfam-ENSKO mice. Mitochondrial dysfunction, therefore, is likely to be an important driving force of neurodegeneration in the ENS and contribute to gastrointestinal symptoms in people with neurodegenerative disorders.
    PLoS ONE 11/2011; 6(11):e27727. DOI:10.1371/journal.pone.0027727 · 3.23 Impact Factor
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    • "did not describe a preferential striatal defect. However, there was substantial degeneration of the striatum, in addition to that observed in the neocortex and hippocampus (Sörensen et al., 2001; Dufour et al., 2008). Most recently, a study looking at the genetic and siRNA ablation of Coenzyme Q in Caenorhabditis elegans noted a particular and specific vulnerability and degeneration of only GABAergic neurons (Earls et al., 2010). "
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    ABSTRACT: Neuronal oxidative phosphorylation (OXPHOS) deficiency has been associated with a variety of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. However, it is not clear how mitochondrial dysfunction alone can lead to a preferential elimination of certain neuronal populations in vivo. We compared different types of neuronal populations undergoing the same OXPHOS deficiency to determine their relative susceptibility and mechanisms responsible for selective neuron vulnerability. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI. The expression of mito-PstI induces double-strand breaks in the mitochondrial DNA (mtDNA), leading to OXPHOS deficiency, mostly due to mtDNA depletion. We targeted mito-PstI expression to the cortex, hippocampus, and striatum under the CaMKII-α promoter. Animals undergoing long-term expression of mito-PstI displayed a selective worsening of the striatum over cortical and hippocampal areas. Mito-PstI expression and mtDNA depletion were not worse in the striatum, but the latter showed the most severe defects in mitochondrial membrane potential, response to calcium, and survival. These results showed that the striatum is particularly sensitive to defects in OXPHOS possibly due to an increased reliance on OXPHOS function in this area and differences in response to physiological stimuli. These results may help explain the neuropathological features associated with Huntington's disease, which have been associated with OXPHOS defects.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2011; 31(27):9895-904. DOI:10.1523/JNEUROSCI.6223-10.2011 · 6.34 Impact Factor
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