Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

The importance of MCU-mediated mitochondrial Ca2+ uptake to the regulation of neuronal bioenergetics and excitability in the brain is demonstrated using single-cell patch-clamp recording and two-photon imaging. Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD(+) to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.

Automated summary

This study demonstrated the importance of MCU-mediated mitochondrial Ca2+ uptake in regulating neuronal bioenergetics and excitability in the brain. The researchers used single-cell patch-clamp recording and two-photon imaging to show that MCU activation promotes energy metabolism and controls excitability in neurons. The study also found that the relationship between MCU activation and firing rate varied between different brain regions.