Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders

Abstract

Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation.

Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer’s Disease

“…To our knowledge, there are no studies assessing the direct effect of lithium on the PPP; nevertheless, its effects on the mitochondrial electron transport chain have been reported previously. Indeed, lithium was shown to promote the activity of three respiratory chain enzymes, complexes I, II, and III in the human frontal cortex [ 58 , 59 ]. Thus, it is possible that lithium altered mitochondrial homeostasis, which caused changes in the NADPH/NADP + ratio [ 60 ].…”

Genetic and Epigenetic Markers of Lithium Response

“…Cells were derived from three patients responders to lithium, three patients not exposed to lithium and three controls. Intriguingly, while the authors found a nonsignificant tendency for lower OCR in cells derived from lithium responder patients compared with controls, in vitro treatment with lithium improved OCR levels by enhancing maximal respiration and reserve capacity exclusively in cells derived from lithium responders [105].…”

“…This is for instance the case of mitochondria [104]. Indeed, a recent study explored the effect of in vitro treatment with lithium on oxygen consumption rate (OCR) and glycolytic rate (two indexes of mitochondrial respiratory function) in iPSC derived neural precursor cells (NPCs) [105]. Cells were derived from three patients responders to lithium, three patients not exposed to lithium and three controls.…”

Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

“…We discuss that the underlying mechanisms might be associated with the aetiology of major depressive disorder. Mitochondrial alterations or altered energy metabolism in iPSC-derived neural lineages has already been studied [24][25][26][27][28][29][30] , but to the best of our knowledge, this is the first report addressing altered energy metabolism in iPSC-derived neural lineages in the context of major depression.…”