Proteolytic control of mitochondrial calcium transport by intermembrane-space proteases

The mitochondrial intermembrane space (IMS) serves as a crucial regulatory junction for mitochondrial calcium (mCa2+) flux. Situated between the outer and inner mitochondrial membranes, the IMS connects cytosolic Ca2+ signals to controlled Ca2+ entry into the matrix. This strategic location enables the IMS to impact mCa2+ transport and Ca2+-dependent mitochondrial metabolism.

Calcium homeostasis within mitochondria is primarily regulated by the mitochondrial calcium uniporter complex (mtCU), which facilitates mCa2+ uptake, and the Na+/Ca2+ exchanger NCLX, responsible for mCa2+ efflux.

Recent research has shed light on the role of IMS proteases in controlling this transport machinery. By employing knockout and overexpression techniques targeting ten IMS proteases (NLN, ATP23, IMMP1L, IMMP2L, YME1L1, OMA1, LACTB2, PARL, and HTRA2), scientists discovered that these proteases influence mtCU components and NCLX levels.

Transcriptomic and proteomic studies revealed that these alterations mainly stem from protease-specific control of transporter stability, rather than transcriptional regulation alone. Additionally, proximity-labeling proteomics uncovered spatial associations between IMS proteases and mCa2+ transport components.

Experimentally, manipulating IMS proteases affected mCa2+ flux and diminished the capacity for mCa2+ retention, indicating impaired protection against Ca2+ overload. These findings collectively establish IMS proteases as a proteostatic regulatory network governing mCa2+ transport and highlight a mechanistic connection between mitochondrial proteostasis and Ca2+ homeostasis.