The Inhibition of ATP Production by Lithium: A Preliminary Study in Whole Mitochondria from Rat Brain and a Putative Model for Bipolar Disorder - Abstract
Lithium is a common and effective treatment and prophylaxis for manic episodes associated with Bipolar Disorder (BD). However, lithium treatments also involve numerous side effects that include nausea, lethargy and renal toxicity. Unfortunately, the development of novel agents to replace lithium in the treatment of BD is impeded because lithium’s pharmacological mode of action is unknown. Here, a novel theory on lithium’s mode of action and BD pathology is developed. Briefly, in response to intracellular proton level fluctuations, lithium ions directly inhibit the excess flow of protons through complex V (ATP synthase) of the oxidative phosphorylation pathway. This, thereby, limits ATP synthesis, reducing biological energy to the cell and body, and provides lithium’s anti-manic effect. Preliminary experiments found that lactic acid can modulate ATP synthesis and that lithium concentrations in the therapeutic range (at < 1.0 mM concentrations) inhibit ATP production dose dependently in whole mitochondria extracted from rat brains. Despite this theory not receiving a full scientific investigation, a putative model is developed and the potential ramifications of this model are discussed to raise awareness of another possibility for lithium’s mode of action so that it can receive further consideration by the neuroscience and medical communities. Investigation of this model may lead to the development of new and better mood stabilizing therapeutics as well as lead to a better understanding of the pathology of complex neural and mental disorders.