Annexin A5 (AnxA5) is a Ca²⁺-dependent phospholipid-binding protein associated with the regulation of intracellular Ca²⁺ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca²⁺ signaling remains elusive. This study reveals a novel function of AnxA5 in regulating mitochondrial Ca²⁺ signaling by localizing at and in the mitochondria and orchestrating intermembrane space Ca²⁺ signaling upon high Ca²⁺ elevations induced by ER Ca²⁺ release. AnxA5 enhances Ca²⁺ flux through the outer mitochondrial membrane by promoting the Ca²⁺-permeable state of VDAC1, shaping mitochondrial ultrastructure and influencing the dynamicity of the mitochondrial Ca²⁺ uniporter. By controlling VDAC1's oligomeric state, AnxA5 protects against cisplatin and selenite-induced apoptotic cell death, highlighting its role as an integral regulator of VDAC1 in physiological and pathological conditions.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier