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<p>Annexin A5 (AnxA5) is a Ca<sup>2+</sup>-dependent phospholipid-binding protein associated with the regulation of intracellular Ca<sup>2+</sup> homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca<sup>2+</sup> signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca<sup>2+</sup> signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca<sup>2+</sup> signaling upon high Ca<sup>2+</sup> elevations induced by ER Ca<sup>2+</sup> 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 Ca<sup>2+</sup> measurements and electrophysiological recordings, AnxA5 was found to enhance Ca<sup>2+</sup> flux through the OMM by promoting the Ca<sup>2+</sup>-permeable state of VDAC1. By modulating intermembrane space Ca<sup>2+</sup> signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca<sup>2+</sup> 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.</p>

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Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月9日

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  • 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

摘要

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.