Mitochondria are fascinating organelles that coordinate cellular metabolism, generate ATP, function in protein quality control and regulate calcium signaling. All of these mitochondrial functions are tightly regulated through signaling events. Sancak laboratory investigates how these diverse set of mitochondrial functions are regulated and coordinated, with a focus on calcium signaling. Our goal is to mechanistically understand rare and common diseases that are caused by mitochondrial dysfunction.
Mitochondria have the ability to take up and store large amounts of calcium. There are at least two immediate consequences of mitochondrial calcium uptake (a) cytosolic signaling events, particularly calcium signaling, are affected (b) mitochondrial energy production is stimulated as a result of activation of the TCA cycle in response to calcium. However, the significance of these events for health and disease remained elusive for a long time, due to poor characterization of mitochondrial calcium uptake machinery.
Recent identification and characterization of the mitochondrial calcium uptake machinery and subsequent loss of function studies point to an important role of this process in health in disease (ref). This machinery is composed of at least five proteins: MCU forms the calcium channel and other components regulate the activity of the channel (Fig1) MCU is pore forming subunit, MICU1 and MICU2 are gatekeeper proteins that block mitochondrial calcium uptake until a certain calcium concentration is reached. MCUb is thought to be a negative regulator of the complex. EMRE is a small protein that is essential for mitochondrial calcium uptake.
Using loss of function studies in cells and animal models, our laboratory studies how mitochondrial calcium uptake regulates cellular signaling, transcription and metabolism. We also aim to understand how this complex machinery is regulated at the transcriptional and post-transcriptional level.