Anti-SLC8B1 monoclonal antibody Made to order

Mitochondrial calcium (Ca-m(2+)) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial(1). Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells(2,3). Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa(2+) overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa(2+) clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa(2+) efflux in cellular function and suggest that augmenting mCa(2+) efflux may be a viable therapeutic strategy in disease.

Impairments in neuronal intracellular calcium (Ca-i(2+)) handling may contribute to Alzheimer's disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (Ca-m(2+)) signaling is a key regulator of both of these processes. Here, we report remodeling of the Ca-m(2+) exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired Ca-m(2+) efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na+/Ca2+ exchanger (NCLX, Slc8b1 gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that Ca-m(2+) overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest Ca-m(2+) exchange as potential therapeutic target in AD.