Influence of mitochondrial enzyme deficiency on adult neurogenesis in mouse models of neurodegenerative diseases

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Neuroscience (Impact Factor: 3.36). 07/2008; 153(4):986-96. DOI: 10.1016/j.neuroscience.2008.02.071
Source: PubMed


Mitochondrial defects including reduction of a key mitochondrial tricarboxylic acid cycle enzyme alpha-ketoglutarate-dehydrogenase complex (KGDHC) are characteristic of many neurodegenerative diseases. KGDHC consists of alpha-ketoglutarate dehydrogenase, dihydrolipoyl succinyltransferase (E2k), and dihydrolipoamide dehydrogenase (Dld) subunits. We investigated whether Dld or E2k deficiency influences adult brain neurogenesis using immunohistochemistry for the immature neuron markers, doublecortin (Dcx) and polysialic acid-neural cell adhesion molecule, as well as a marker for proliferation, proliferating cell nuclear antigen (PCNA). Both Dld- and E2k-deficient mice showed reduced Dcx-positive neuroblasts in the subgranular zone (SGZ) of the hippocampal dentate gyrus compared with wild-type mice. In the E2k knockout mice, increased immunoreactivity for the lipid peroxidation marker, malondialdehyde occurred in the SGZ. These alterations did not occur in the subventricular zone (SVZ). PCNA staining revealed decreased proliferation in the SGZ of E2k-deficient mice. In a transgenic mouse model of Alzheimer's disease, Dcx-positive cells in the SGZ were also reduced compared with wild type, but Dld deficiency did not exacerbate the reduction. In the malonate lesion model of Huntington's disease, Dld deficiency did not alter the lesion-induced increase and migration of Dcx-positive cells from the SVZ into the ipsilateral striatum. Thus, the KGDHC subunit deficiencies associated with elevated lipid peroxidation selectively reduced the number of neuroblasts and proliferating cells in the hippocampal neurogenic zone. However, these mitochondrial defects neither exacerbated certain pathological conditions, such as amyloid precursor protein (APP) mutation-induced reduction of SGZ neuroblasts, nor inhibited malonate-induced migration of SVZ neuroblasts. Our findings support the view that mitochondrial dysfunction can influence the number of neural progenitor cells in the hippocampus of adult mice.

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Available from: Magali Dumont, Mar 25, 2014
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    • "). Gene-specific quantitative PCR and bisulfite sequencing confirmed the altered expression and methylation of several genes involved in neural progenitor proliferation, neuroprotection, and mitochondria function, including Galanin, Ng2, Ngb, Kctd14, and Atp5h (Abbosh et al., 2011; Burmester et al., 2000; Calingasan et al., 2008; Kucharova and Stallcup, 2010) (Figures 4D and 4E). "
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    Cell stem cell 06/2013; 13(2). DOI:10.1016/j.stem.2013.05.006 · 22.27 Impact Factor
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    • "This may be because KGDHC increases after birth and does not reach adult levels until 30 days (Buerstatte et al. 2000; Yang et al. 2009). In addition, DLST +/− mice have normal brain morphology, with no evident neurodegenerative changes or astrogliosis (Calingasan et al. 2008). In the current study, DLST +/− and wildtype mice were injected with [U-13 C]glucose, and metabolite concentrations and 13 C labelling patterns were mapped using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography -mass spectrometry, high performance liquid chromatography and a glucose assay. "
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    ABSTRACT: The activity of the α-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme complex that mediates the oxidative decarboxylation of α-ketoglutarate in the TCA cycle, is reduced in Alzheimer's disease. We investigated the metabolic effects of a partial KGDHC activity reduction on brain glucose metabolism using mice with disrupted expression of dihydrolipoyl succinyltransferase (DLST; gene encoding the E2k subunit of KGDHC). Brain tissue extracts from cortex and cerebellum of 6-week-old heterozygote DLST knockout mice (DLST+/-) and corresponding wild-type mice injected with [U-(13) C]glucose and decapitated 15 min later were analyzed. An increase in the concentration of glucose in cortex suggested a decrease in the cortical utilization of glucose in DLST+/- mice. Furthermore, the concentration and (13) C labelling of aspartate in cortex were reduced in DLST+/- mice. This decline was likely caused by a decrease in the pool of oxaloacetate. In contrast to results from cell culture studies, no indications of altered glycolysis or GABA shunt activity were found. Glucose metabolism in the cerebellum was unaffected by the decrease in KGDHC activity. Among metabolites not related to glucose metabolism, the concentration of taurine was decreased in the cortex, and that of tyrosine was increased in the cerebellum. These results imply that diminished KGDHC activity has the potential to induce the reduction in glucose utilization that is seen in several neurodegenerative diseases.
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    • "The results of recent in vivo studies suggest that mitochondrial function might play an important role in the process of neurogenesis both during development and in adulthood. Mice deficient in mitochondrial KGDH complex had fewer Dcx + neuronal progenitor cells (Calingasan et al., 2008) and thiamine deficiency impaired hippocampal neurogenesis and caused cognitive dysfunction in adult mice (Zhao et al., 2008). Thiamine deficiency has long been appreciated to cause Wernicke-Korsakoff syndrome, a form of encephalopathy and psychosis, which is characterized by reduced activity of the KGDH complex in the brain (Gibson et al., 1984). "
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    ABSTRACT: The impairment of hippocampal neurogenesis has been linked to the pathogenesis of neurological disorders from chronic neurodegenerative disease to the progressive cognitive impairment of children who receive brain irradiation. Numerous studies provide evidence that inflammation downregulates neurogenesis, with multiple factors contributing to this impairment. Although mitochondria are one of the primary targets of inflammatory injury, the role of mitochondrial function in the modulation of neurogenesis remains relatively unstudied. In this study, we used neurosphere-derived cells to show that immature doublecortin (Dcx)-positive neurons are uniquely sensitive to mitochondrial inhibition, demonstrating rapid loss of mitochondrial potential and cell viability compared with glial cells and more mature neurons. Mitochondrial inhibition for 24 h produced no significant changes in astrocyte or oligodendrocyte viability, but reduced viability of mature neurons by 30%, and reduced survival of Dcx(+) cells by 60%. We demonstrate that protection of mitochondrial function with mitochondrial metabolites or the mitochondrial chaperone mtHsp75/mortalin partially reverses the inflammation-associated impairment of neurogenesis in vitro and in irradiated mice in vivo. Our findings highlight mitochondrial mechanisms involved in neurogenesis and indicate mitochondria as a potential target for protective strategies to prevent the impairment of neurogenesis by inflammation.
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