Introduction and Aims
Lithium salts are established medications in a variety of mental health conditions. The molecular mode of action if lithium is incompletely understood. Many cellular effects associated with lithium treatment are linked to mitochondrial function. We investigated the effects of lithium on mitochondrial calcium handling due to its obvious role in neuronal signaling.
Methods
We investigated the calcium capacity of mitochondria from murine mouse liver in the presence and absence of lithium, both in its natural composition and as pure 6-lithium and 7-lithium. To achieve this, we utilized high-resolution respirometry and fluorometry techniques. Additionally, we examined the subcellular distribution of lithium isotopes using inductively coupled plasma mass spectrometry and nanoscale secondary ion mass spectrometry. Furthermore, we analyzed the formation of amorphous calcium phosphate, both in the presence and absence of lithium isotopes, using 31-phosphorus nuclear magnetic resonance and dynamic light scattering.
Results
Lithium protected against calcium-induced permeability transition (32.84±11.2 min to onset vs 15.69±7.3 min to onset, errors: SD, n=8, p>0.001) and decreased calcium capacity of liver mitochondria (589.8±99.1 nmol/mg vs 635.7±100.3 nmol/mg, errors: SD, n=10, p<0.01) at clinically relevant concentrations. Interestingly, brain mitochondrial calcium capacity was increased, not decreased, by lithium (601.3±64.8 nmol/mg vs 463.2±34.5 nmol/mg, errors: SD, n=5, p<0.01). Further analyses revealed that 7-lithium was more effective than 6-lithium in altering calcium capacity, whereas 6-lithium was more effective in delaying permeability transition. Interestingly, these effects were not attributed to differences in lithium isotope distribution within cells or subcellular compartments. Instead, our in vitro experiments demonstrated that lithium isotopes had distinct effects on the size distribution of amorphous calcium phosphate colloids, which is a plausible mechanism underlying the isotope-specific mitochondrial calcium capacities observed in our study.
Conclusion
We identified mitochondrial calcium management as a plausible component of clinical lithium effects and found evidence for a direct interaction of lithium with amorphous calcium phosphate aggregation. The isotope-specificity of lithium effects provide a promising avenue for the development of more effective lithium-based drugs.