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Abstract
Mitochondrial Ca2+ ([Ca2+]M) uptake through its Ca2+ uniporter (MCU) is central to many cell functions such as bioenergetics, spatiotemporal organization of Ca2+ signals, and apoptosis. MCU activity is regulated by several intrinsic proteins including MICU1, MICU2, and EMRE. While significant details about the role of MICU1, MICU2, and EMRE in MCU function have emerged recently, a key challenge for the future experiments is to investigate how these regulatory proteins modulate mitochondrial Ca2+ influx through MCU in intact cells under pathophysiological conditions. This is further complicated by the fact that several variables affecting MCU function change dynamically as cell functions. To overcome this void, we develop a data-driven model that closely replicates the behavior of MCU under a wide range of cytosolic Ca2+ ([Ca2+]C), [Ca2+]M, and mitochondrial membrane potential values in WT, MICU1 knockout (KO), and MICU2 KO cells at the single mitochondrion and whole-cell levels. The model is extended to investigate how MICU1 or MICU2 KO affect mitochondrial function. Moreover, we show how Ca2+ buffering proteins, the separation between mitochondrion and Ca2+-releasing stores, and the duration of opening of Ca2+-releasing channels affect mitochondrial function under different conditions. Finally, we demonstrate an easy extension of the model to single channel function of MCU.
Highlights
Mitochondrial Ca2+ uptake plays a central role in cell metabolism, signaling, and survival [1,2,3].entry into the matrix is mediated by the Ca2+ uniporter-channel complex with a high selectivity for Ca2+ and large carrying capacity [4,5,6,7,8]
To assess how mitochondrial Ca2+ uptake protein 1 (MICU1) or MICU2 KO affect mitochondrial function, we extend the model to incorporate the dynamics of mitochondrial NADH concentration ([NADH]M ), mitochondrial ADP
We remark that our fitting criterion searches for the parameters that result in the best fit to all observations simultaneously
Summary
Entry into the matrix is mediated by the Ca2+ uniporter-channel complex with a high selectivity for Ca2+ and large carrying capacity [4,5,6,7,8]. This complex consists of mitochondrial Ca2+ uniporter (MCU), which constitutes the pore-forming subunit of the channel [5,9]. MCU interacts with several intrinsic proteins that regulate its activity These include mitochondrial Ca2+ uptake protein 1. While MICU3 is largely restricted to brain, MICU1 and MICU2 are widely expressed and play major roles in mitochondrial Ca2+ uptake in most human cells [13,14]. EMRE has been shown to play a key role in the regulation of MCU activity in the mitochondrial Ca2+ concentration ([Ca2+ ]M )-dependent manner [17,18,19]
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