Altered mitochondrial Ca 2+uptake in presynaptic terminals of cultured striatal and cortical neurons from the zQ175 knock-in mouse model of Huntington 's disease

Calcium (Ca 2 + ) in mitochondria plays crucial roles in neurons including modulating metabolic processes. Moreover, excessive Ca 2 + in mitochondria can lead to cell death. Thus, altered mitochondrial Ca 2 + regulation has been implicated in several neurodegenerative diseases including Huntington ' s disease (HD). HD is a progressive hereditary neurodegenerative disorder that results from abnormally expanded cytosine -adenine -guanine trinucleotide repeats in the huntingtin gene. One neuropathological hallmark of HD is neuronal loss in the striatum and cortex. However, mechanisms underlying selective loss of striatal and cortical neurons in HD remain elusive. Here, we measured the basal Ca 2 + levels and Ca 2 + uptake in single presynaptic mitochondria during 100 external electrical stimuli using highly sensitive mitochondria -targeted Ca 2 + indicators in cultured cortical and striatal neurons of a knock -in mouse model of HD (zQ175 mice). We observed elevated presynaptic mitochondrial Ca 2 + uptake during 100 electrical stimuli in HD cortical neurons compared with wild -type (WT) cortical neurons. We also found the highly elevated presynaptic mitochondrial basal Ca 2 + level and Ca 2 + uptake during 100 stimuli in HD striatal neurons. The elevated presynaptic mitochondrial basal Ca 2 + level in HD striatal neurons and Ca 2 + uptake during stimulation in HD striatal and cortical neurons can disrupt neurotransmission and induce mitochondrial Ca 2 + overload, eventually leading to neuronal death in the striatum and cortex of HD.