Kenneth R. Norman, PhD

We have recently demonstrated that SEL-12, the C. elegans presenilin ortholog, has a role in mediating endoplasmic reticulum-mitochondrial Ca²⁺ homeostasis. Disruption of presenilin function results in an increase in mitochondrial Ca²⁺ levels and alters mitochondrial metabolism promoting protein homeostasis collapse and neurodegeneration. Presenilin is a highly conserved protein found from plants to humans that is extensively found on endomembrane structures (e.g., endoplasmic reticulum and lysosome) of most cell types. However, the role presenilin has in the endomembrane system is not clear. Importantly, mutations in human presenilin are the most common cause of early onset familial Alzheimer’s disease. Despite the identification of the involvement of presenilin in Alzheimer’s disease over 20 years ago, the functional consequences of mutations in presenilin causing Alzheimer’s disease are not understood. Thus, we are employing C. elegans to determine the role presenilin has in mediating mitochondrial Ca²⁺ homeostasis.

Since we have found a fundamental role of mitochondrial Ca²⁺ homeostasis in mediating neuronal health, we are investigating the mitochondrial Ca²⁺ uniporter complex (MCUcx). Ca²⁺ uptake into the mitochondria is mediated by the evolutionarily conserved mitochondrial Ca²⁺ uniporter complex (MCUcx). The MCUcx is composed of four core components: the pore forming MCU protein, an auxiliary subunit EMRE (essential for MCU regulator) and the gatekeepers MICU1 and MICU2/3. With the recent molecular identification of MCUcx components, many current studies have implicated altered mitochondrial Ca²⁺homeostasis as having a fundamental role in promoting neurodegeneration. Thus, we are exploiting the genetic amenability and simplicity of C. elegans to interrogate the role of the four core components of the MCUcx to establish a foundation of MCUcx function in an in vivo model system and to discover new gene products that are involved in mitochondrial calcium influx.