Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.

Area of Science:

• Cellular Metabolism
• Mitochondrial Respiration
• Biochemistry

Background:

• Oxidative phosphorylation (OXPHOS) dysfunction can be managed by reversing succinate dehydrogenase (complex II) to maintain the Coenzyme Q (Q)-pool redox state.
• The role of complex II assembly factors in cellular adaptation to mitochondrial stress is not fully understood.

Purpose of the Study:

• To investigate the role of SDHAF2 protein, a complex II assembly factor, in metabolic adaptation during acute mitochondrial complex III dysfunction.
• To understand how SDHAF2 influences the tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) signaling, and cellular growth under OXPHOS stress.

Main Methods:

• Utilized HEK293T cells with inhibited complex III to study metabolic responses.
• Assessed the impact of SDHAF2 loss on TCA cycle directionality, ROS production, glycolytic adaptation, and cell growth.
• Compared metabolic phenotypes of SDHAF2-deficient cells with glycolysis-adapted cells under Q-pool stress.

Main Results:

• SDHAF2 loss during complex III inhibition resulted in a reductive TCA cycle, loss of SDHA-derived ROS signaling, inadequate glycolytic adaptation, and severe growth impairment.
• Cells adapted to glycolysis under Q-pool stress did not accumulate SDHAF2 and showed mild growth phenotypes irrespective of SDHAF2 levels.
• SDHAF2 is critical for maintaining TCA cycle dynamics and ROS signaling for overcoming OXPHOS dysfunction.

Conclusions:

• SDHAF2 protein is essential for cellular metabolic adaptation to acute OXPHOS dysfunction.
• Complex II assembly, mediated by SDHAF2, balances TCA cycle directionality, protects against Q-pool stress, and enables ROS-mediated signaling.
• Understanding SDHAF2's role provides insights into cellular strategies for surviving mitochondrial respiratory stress.