Complex II assembly drives metabolic adaptation to OXPHOS dysfunction
- Roopasingam Kugapreethan
- Sheik Nadeem Elahee Doomun
- Joanna Sacharz
- Ann E. Frazier
- Tanavi Sharma
- Yau Chung Low
- Shuai Nie
- Michael G. Leeming
- Linden Muellner-Wong
- Karena Last
- Tegan Stait
- David P. De Souza
- David R. Thorburn
- Malcolm J. McConville
- David A. Stroud
2025-08-15
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.