The Role Of Micu1 In Neuronal Mitochondrial Calcium Homeostasis And Function

Mitochondrial Ca2+ homeostasis controls intracellular calcium signals, cellular energy production and mechanisms of cell death. We and others have shown that MICU1 is an intermembrane space protein that provides Ca2+ sensitivity to Ca2+ uptake by the mitochondria through the mitochondrial Ca2+ uniporter. Specifically, MICU1 is required both for protecting mitochondria from Ca2+ uptake when the cytoplasmic [Ca2+] is low and for proper transmission of the short-lasting Ca2+ signal from the ER/SR to the mitochondria. Human loss of function mutation of MICU1 has been linked to learning difficulties, skeletal muscle weakness, fatigue and motoric impairment.In this study, we describe and validate a neuron-specific MICU1 KO model in mice. Proteomic analysis of the mitochondria confirms loss of MICU1 and indicates a possible compensatory mechanism for the loss of MICU1 by other constituents of the uniporter. Behavioral tests performed on the animals showed decreased motoric function progressing with age. Measurements of cytoplasmic and mitochondrial Ca2+ signals in cultured cortical neurons and Ca2+ uptake by isolated mitochondria revealed altered Ca2+ homeostasis which might underlie the functional impairments.Our results reveal the specific contributions of MICU1 in neuronal Ca2+ homeostasis and provide some clues to the neuronal pathogenesis in MICU1 loss of function patients.