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.