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SHR Neuro Krebs Kardio Lipid Stoffw 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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Führende Autor*innen der Med Uni Graz

Graier Wolfgang

Oflaz Furkan Enes

Co-Autor*innen der 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

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