Abstract
Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer’s disease. Here we demonstrate that deletion of forebrain MTCH2 increases mitochondria and whole-body energy metabolism, increases locomotor activity, but impairs motor coordination and balance. Importantly, mice deficient in forebrain MTCH2 display a deficit in hippocampus-dependent cognitive functions, including spatial memory, long term potentiation (LTP) and rates of spontaneous excitatory synaptic currents. Moreover, MTCH2-deficient hippocampal neurons display a deficit in mitochondria motility and calcium handling. Thus, MTCH2 is a critical player in neuronal cell biology, controlling mitochondria metabolism, motility and calcium buffering to regulate hippocampal-dependent cognitive functions.
Highlights
Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer’s disease
We demonstrate that Mitochondrial carrier homolog 2 (MTCH2) is a critical player in hippocampal neuronal biology, modulating mitochondrial structure, function and motility to result in changes in cognitive functions
One of the early symptoms of Alzheimer’s disease (AD) is loss of memory, and in this study, we found that MTCH2 deficiency in the forebrain leads to hippocampal-dependent cognitive deficits already in young mice, which correlated with a reduction in synaptic connectivity and an impaired hippocampal long term potentiation (LTP)
Summary
Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer’s disease. In that study and in an earlier one performed in the hematopoietic system[14] we showed that loss of MTCH2 increases many parameters related to mitochondria function including oxidative phosphorylation (OXPHOS), mitochondrial size, and the levels of ATP, NADH and reactive oxygen species (ROS). Taken together, these findings indicate that MTCH2 is a pivotal regulator of mitochondria and whole-body energy metabolism. MTCH2 locus shows gene-based genome-wide significant association with Alzheimer’s disease (AD)[23,24,25], and MTCH2 expression levels decrease in AD cases in parallel www.nature.com/scientificreports/
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