Mitochondrial Calcium Uptake: Context Matters

Abstract

Mitochondrial calcium (Ca2+) fluxes regulate ATP generation, contribute to the regulation of apoptosis, and when very large can play a role in buffering changes in intracellular Ca2+ concentration ([Ca2+]i). However, fundamental disagreements on the extent and speed of Ca2+ uptake by mitochondria have been reported. The reliability and consistency mitochondrial Ca2+ uptake measurements is consequently critical for our understanding of cell biology and pathology in cells from all tissue including heart, neurons, and kidney. Importantly, measurement of Ca2+ movement across the inner mitochondrial membrane (IMM) has been dramatically enhanced by the molecular identification of the mitochondrial Ca2+ uniporter (MCU) and the mitochondrial Na+/Ca2+ exchanger (NCLX). First, we quantitatively analyze cardiac mitochondrial Ca2+ uptake experiments from the literature. We then interpret the results with respect to measurements conducted on recent MCU candidates which suggest that the conductance of a single MCU is ∼6-7 pS (in 105 mM [Ca2+]). Our quantitative analysis suggests three clear findings: 1. Under physiological conditions, Ca2+ influx into mitochondria is small and is dwarfed by other cytosolic Ca2+ extrusion pathways; 2. MCU-dependent Ca2+ uptake appears to be dependent on [Ca2+]i under physiological conditions; 3. There appear to be hundreds of MCU channels per mitochondrion but they are predominantly closed under physiological conditions. We conclude that under physiological conditions mitochondria do not act as a significant Ca2+ buffers in heart despite being capable of substantial Ca2+ accumulation if non-physiological conditions favor prolonged levels of high extra-mitochondrial [Ca2+].