Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis
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.
Authors
- Varda Shoshan‐Barmatz (ORCID: https://orcid.org/0000-0002-6756-4340)
- Bent Brachvogel (ORCID: https://orcid.org/0000-0002-3923-0554)
- Johannes Pilic (ORCID: https://orcid.org/0000-0001-8452-0879)
- Susanne Summerauer
- René Rost (ORCID: https://orcid.org/0000-0002-5393-0370)
- Markus Waldeck‐Weiermair (ORCID: https://orcid.org/0000-0002-5792-6766)
- Wolfgang F. Graier (ORCID: https://orcid.org/0000-0003-1871-3298)
- Eva Bernhart (ORCID: https://orcid.org/0000-0002-5675-857X)
- Furkan Enes Oflaz (ORCID: https://orcid.org/0000-0002-1130-8970)
- Benjamin Gottschalk (ORCID: https://orcid.org/0000-0001-5588-7698)
- Roland Malli (ORCID: https://orcid.org/0000-0001-6327-8729)
- Alexander I. Bondarenko
- Zhanat Koshenov (ORCID: https://orcid.org/0000-0002-2790-7126)
- Snježana Radulović (ORCID: https://orcid.org/0000-0002-6791-8620)
- Michael Trenker (ORCID: https://orcid.org/0009-0003-9801-6624)
- Gerd Leitinger (ORCID: https://orcid.org/0000-0002-5281-9830)
- Martin Hirtl (ORCID: https://orcid.org/0000-0002-4322-5758)
- Aditya Karunanithi Nivedita (ORCID: https://orcid.org/0009-0009-8472-8683)
- Adlet Sagintayev (ORCID: https://orcid.org/0009-0003-8444-4409)
Institutions
- Ben-Gurion University of the Negev (IL)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Cologne (DE)
- Medical University of Graz (AT)
- Cornell University (US)
- BioTechMed-Graz (AT)
- University Hospital Cologne (DE)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1038/s44318-025-00454-9
- Citations
- 8
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Deutsche Forschungsgemeinschaft
- Austrian Science Fund
- Israel Science Foundation