BPS2026 – Molecular insights into mitochondrial calcium extrusion

Mitochondrial calcium is a critical regulator of cellular function. Adequate levels of mitochondrial calcium are required for ATP production, while excess calcium triggers cell death. Matrix calcium levels are carefully maintained within a homeostatic range through the coordinated activity of uptake and efflux pathways. Dysregulation of these pathways is implicated in cardiovascular and neurodegenerative pathologies. While the mechanisms of mitochondrial calcium uptake are well-characterized, the efflux mechanisms are less understood. NCLX has been widely regarded as a key mitochondrial calcium efflux transporter. To investigate the transport mechanism of NCLX, we used cryo-electron microscopy to resolve high-resolution structures of NCLX in multiple mechanistically informative states. Our structures reveal the molecular basis of calcium binding and selectivity of NCLX. Moreover, examination of different conformational states unveils a unique alternating access mechanism for calcium translocation. This work advances our understanding of mitochondrial calcium regulation and establishes a foundation for developing therapies for diseases arising from aberrant mitochondrial calcium handling.