From direct to indirect lithium targets: a comprehensive review of omics data.

Metal ions are critical to a wide range of biological processes. Among them, lithium (Li) has been recognised for its benefit as a treatment for bipolar disorder (BD). However, we are yet to grasp the extent of its role in biological processes, despite its molecular targets having been extensively studied. Here we review a wide range of transcriptomic, proteomic and metabolomic studies in order to obtain a full picture of Li effects at various levels. Multifarious patterns of Li-regulated genes, proteins and metabolites are identified. Some of these patterns are explained as the outcomes of individual Li targets. For instance, Li inhibition of GSK-3 has a wide range of effects: axis development in embryos; cell and tissue differentiation, in particular neurogenesis and osteogenesis; or control of apoptosis. This results in neuroprotection and an attenuation of cognitive deficits. Lithium plays an important role in mitochondrial function, which it improves via its role in phospholipid metabolism and inositol depletion. This is also seen in metabolomics, where its role in the mitochondrial respiratory chain influences energy production and oxidative stress. Lithium also affects the proteins involved in the processing of APP, thus highlighting a possible involvement in Alzheimer's disease. Finally, Li also impacts lipid homeostasis, with studies showing that environmental exposure can impact lipid transport and prostaglandin synthesis. It is seldom possible to establish a causal relationship between Li targets at the molecular level and the resulting effects at the system level. For example, Li effects on adenylate cyclase regulation are not easily linked to any omic pattern despite the importance of the adenylate pathway. Nevertheless, refining our knowledge on the cellular functions of individual Li targets would improve our understanding and interpretation of omics data. This review demonstrates that Li is key to a wide range of processes at all levels, from neuroprotection to oxidative stress and energy production. A corollary of this work is the need for an increased awareness of environmental issues related to Li industrial wastes, in particular considering the widespread use of this metal in our modern society.