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SHR Neuro Cancer Cardio Lipid Metab Microb

Oflaz, FE; Bondarenko, AI; Trenker, M; Waldeck-Weiermair, M; Gottschalk, B; Bernhart, E; Koshenov, Z; Radulović, S; Rost, R; Hirtl, M; Pilic, J; Karunanithi, Nivedita, A; Sagintayev, A; Leitinger, G; Brachvogel, B; Summerauer, S; Shoshan-Barmatz, V; Malli, R; Graier, WF.
Annexin A5 controls VDAC1-dependent mitochondrial Ca²⁺ homeostasis and determines cellular susceptibility to apoptosis.
EMBO J. 2025; Doi: 10.1038/s44318-025-00454-9
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Leading authors Med Uni Graz: Graier Wolfgang; Oflaz Furkan Enes
Co-authors Med Uni Graz: Bernhart Eva Maria; Bondarenko Oleksandr; Gottschalk Benjamin; Hirtl Martin; Koshenov Zhanat; Leitinger Gerd; Malli Roland; Pilic Johannes; Radulovic Snjezana; Rost René; Sagintayev Adlet; Trenker Michael; Waldeck-Weiermair Markus
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Abstract:: 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. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca²⁺ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca²⁺ signaling upon high Ca²⁺ elevations induced by ER Ca²⁺ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca²⁺ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca²⁺ flux through the OMM by promoting the Ca²⁺-permeable state of VDAC1. By modulating intermembrane space Ca²⁺ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca²⁺ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.
Find related publications in this database (Keywords): Annexin-A5; VDAC1 Ca2+ Permeability; Intermembrane Space Ca-2(+) Signaling; Apoptotic Cell Death