Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus

Abstract

Emerging evidence suggests that mitochondrial dynamics regulates adult hippocampal neurogenesis (AHN). Although abnormal AHN has been linked to depression, anxiety, and cognitive dysfunction, which are features of neurodegenerative conditions, including Parkinson's disease (PD), the impact of mitochondrial deficits on AHN have not been explored previously in a model of neurodegeneration. Here, we used PTEN-induced kinase 1-deficient ( ) mice that lacked a mitochondrial kinase mutated in recessive familial PD. We show that mitochondrial defects, elevated glycolysis, and increased apoptosis are associated with impaired but not abrogated differentiation of PINK1-deficient neural stem cells (NSCs) in culture. In the dentate gyrus of mice, newly generated doublecortin-positive neurons show aberrant dendritic morphology, and their maturation is compromised compared with wild-type mice. In addition, labeling of NSCs with 5-ethynyl-2'-deoxyuridine shows that proliferating NSC numbers are normal, but the differentiation of NSCs to doublecortin-positive neuroblasts and mature NeuN neurons is impeded in mice. Finally, we demonstrate that home cage activity and corticosterone levels of mice are normal, thereby excluding reduced physical activity and increased stress as causes of neurogenesis defects. Our results reveal a new and important relationship between mitochondrial dysfunction and impaired AHN in a genetic PD model. Targeting mitochondrial function and metabolism to increase AHN may hold promise for the treatment of affective disorders and the mitigation of related symptoms in PD and other neurodegenerative conditions.-Agnihotri, S. K., Shen, R., Li, J., Gao, X., Büeler, H. Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus.

Intergenerational transmission of the positive effects of physical exercise on brain and cognition

“…The enhanced mitochondrial activity in the offspring might contribute to the cellular and behavioral changes observed in the pre-sent study. This is supported by recent works reporting that mitochondrial integrity is crucial for cell differentiation and dendritogenesis of newborn neurons (31) and for efficient lineage progression of adult NSCs in adult and aged hippocampus (32), as well as the finding that acute activation or deactivation of certain mitochondrial receptors is sufficient to modify memory abilities in adult mice (33). We believe that the fact that the mtDNA/nDNA ratio is not altered in the hippocampus of the offspring but that differences are found in the same samples in citrate synthase activity is remarkable and might reflect differences in mitochondrial functionality rather than differences in the number of mitochondria.…”

Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity

“…Mitochondria support important aspects of neuronal development, such as axonal (Spillane et al, 2013) and dendritic branching (Agnihotri et al, 2017). We assessed the effects of m.3243A>G variant on somatodendritic neuronal structure by sparsely transfecting iNeurons at DIV 6 with a construct expressing red fluorescent protein ( Fig.…”

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

“…Parkinson's disease (Agnihotri et al, 2017;Lee et al, 2017;Verma et al, 2018). Epilepsy is a frequent presentation of MELAS.…”