BPS2026 – TMEM65 reconstitutes mitochondrial Na+/Ca2+ exchange

Since the 1970s, mitochondria have been known to export Ca 2+ via a transport process coupled to Na + import (mito-NCX). It has long been recognized that mito-NCX is a key contributor to intracellular Ca 2+ homeostasis and signaling, but the molecular basis for this function was unclear. Here, we show that TMEM65, recently implicated to be important for mito-NCX, itself functions as a Na + /Ca 2+ exchange transporter. Heterologous expression of TMEM65 imparts mito-NCX in cells otherwise lacking endogenous activity. Furthermore, reconstituting purified TMEM65 in liposomes results in Na + /Ca 2+ exchange transport recapitulating classical, biochemical hallmarks of mito-NCX. Together, these findings demonstrate TMEM65 itself is sufficient for Na + /Ca 2+ exchange and provides a molecular basis for mito-NCX activity.