ABNORMAL CALCIUM HOMEOSTASIS AND MITOCHONDRIAL POLARIZATION IN A HUMAN ENCEPHALOMYOPATHY

Patients with several inherited human encephalomyopathies exhibit syst emic and neurological symptoms in association with specific mitochondr ial mutations. The mechanisms by which these mitochondrial mutations r esult in cellular injury have not been elucidated. One potential cause of neuronal vulnerability is an inability to effectively buffer intra cellular calcium. We report that fibroblasts from patients with one sp ecific inherited encephalomyopathy, MELAS (mitochondrial encephalomyop athy, lactic acidosis, and stroke-like episodes) syndrome, have elevat ed levels of ionized calcium and cannot normally sequester calcium inf luxes. Quantitative fluorescence imaging demonstrated that this abnorm ality was associated with a relative decrease in mitochondrial membran e potential compared to control fibroblasts. This documentation of pat hological calcium homeostasis in a genetic neurological disease extend s the calcium hypothesis of toxic cell injury to human mitochondrial e ncephalomyopathies.