Complex II assembly drives metabolic adaptation to OXPHOS dysfunction
During acute oxidative phosphorylation (OXPHOS) dysfunction, reversal of succinate dehydrogenase (complex II) maintains the redox state of the Coenzyme Q (Q)-pool by using fumarate as terminal electron acceptor in certain tissues and cell lines. We identified the action of SDHAF2 protein, a complex II assembly factor, as critical for metabolic adaptation during complex III dysfunction in HEK293T cells. SDHAF2 loss during complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site-derived reactive oxygen species (ROS) signaling, insufficient glycolytic adaptation, and a severe growth impairment. Glycolysis adapted cells, however, did not accumulate SDHAF2 upon Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes regardless of SDHAF2 presence. Thus, our study reveals how complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to use ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.
Authors
- Sheik Nadeem Elahee Doomun (ORCID: https://orcid.org/0000-0002-6384-859X)
- Michael G. Leeming (ORCID: https://orcid.org/0000-0001-8981-0701)
- Yau Chung Low (ORCID: https://orcid.org/0009-0009-9799-2993)
- Roopasingam Kugapreethan (ORCID: https://orcid.org/0000-0002-4224-5749)
- David A. Stroud (ORCID: https://orcid.org/0000-0002-2048-3383)
- Shuai Nie (ORCID: https://orcid.org/0000-0003-0028-5504)
- Linden Muellner-Wong (ORCID: https://orcid.org/0000-0003-0348-6408)
- David R. Thorburn (ORCID: https://orcid.org/0000-0002-7725-9470)
- Malcolm J. McConville (ORCID: https://orcid.org/0000-0002-7107-7887)
- Joanna Sacharz (ORCID: https://orcid.org/0000-0002-1808-747X)
- Tegan Stait
- Ann E. Frazier (ORCID: https://orcid.org/0000-0002-6491-3437)
- Tanavi Sharma (ORCID: https://orcid.org/0000-0002-6054-315X)
- David P. De Souza (ORCID: https://orcid.org/0000-0002-7225-2632)
- Karena Last (ORCID: https://orcid.org/0000-0002-4396-8404)
Institutions
- Royal Children's Hospital (AU)
- The University of Melbourne (AU)
- Victorian Clinical Genetics Services (AU)
- Murdoch Children's Research Institute (AU)
Publication Details
- Journal
- Science Advances
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1126/sciadv.adr6012
- Citations
- 4
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.75