The FASEB JournalResearch Communication Pancreatic -cell Na channels control global Ca 2 signaling and oxidative metabolism by inducing Na and Ca 2 responses that are propagated into mitochondria

Communication between the plasma membrane and mitochondria is essential for initiating the Ca 2 and metabolic signals required for secretion in cells. Although voltage-dependent Na channels are abundantly expressed in cells and activated by glucose, their role in communicating with mitochondria is unresolved. Here, we combined fluorescent Na, Ca 2 , and ATP imaging, electrophysiological analysis with tetrodotoxin (TTX)-dependent block of the Na channel, and molecular manipulation of mitochondrial Ca 2 transporters to study the communication between Na channels and mitochondria. We show that TTX inhibits glucose-dependent depolarization and blocks cytosolic Na and Ca 2 responses and their propaga- tion into mitochondria. TTX-sensitive mitochondrial Ca 2 influx was largely blocked by knockdown of the mitochondrial Ca 2 uniporter (MCU) expression. Knockdown of the mitochondrial Na/Ca 2 exchanger (NCLX) and Na dose response analysis demonstrated that NCLX mediates the mitochondrial Na influx and is tuned to sense the TTX-sensitive cytosolic Na responses. Finally, TTX blocked glucose-dependent mitochondrial Ca 2 rise, mitochondrial metabolic ac- tivity, and ATP production. Our results show that communication of the Na channels with mitochondria shape both global Ca 2 and metabolism signals linked