Complex II assembly drives metabolic adaptation to OXPHOS dysfunction
Summary
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 | Kugapreethan R, Elahee Doomun SN, Sacharz J, Frazier AE, Sharma T, Low YC, Nie S, Leeming MG, Muellner-Wong L, Last K, Stait T, De Souza DP, Thorburn DR, McConville MJ, Stroud DA |
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| Journal | Science advances |
| Publication Date | 2025 Aug 15;11(33):eadr6012 |
| PubMed | 40815660 |
| PubMed Central | PMC12356253 |
| DOI | 10.1126/sciadv.adr6012 |