Complex IV inhibitors reprogram root growth and induce mitophagy in Arabidopsis

Electrons harvested from food are carried to the electron transport chain (ETC) to drive cellular energy production. The rate-limiting enzyme of mitochondrial ETC (mtETC/mETC) is cytochrome c oxidase (CcO)/Complex IV. Complex IV deficiency leads to severe human diseases and plant lethality, yet how Complex IV inhibition affects mitochondrial dynamics and cellular homeostasis remains unclear. Using two thiamine pyrophosphate-thiazole (TPP thiazole, TPPT) derivatives that specifically target mitochondria and reversibly inhibit Complex IV, we show that TPPT treatment inhibits primary root growth in Arabidopsis in an auxin- and ATP-dependent manner. Furthermore, moderate TPPT treatment leads to partial depolarization of mitochondria and induces autophagy and mitophagy, whereas excessive TPPT disrupts vacuolar dynamics and inhibits mitophagy. In summary, TPPT derivatives as mild Complex IV inhibitors are useful tools for dissecting cellular remodeling upon energy deficiency and for the study of mitophagy. A study uses reversible Complex IV inhibitors (TPPT) to investigate how mitochondrial inhibition affects root growth, endomembrane trafficking, and mitophagy in Arabidopsis, finding that TPPT has dose-dependent effects on mitochondrial function and degradation, inducing both macro- and micro-mitophagy.