Fig. 3

Schematic representation of Drp1 regulating multiple mitochondrial bioenergetic processes by inducing mitochondrial calcium overload in ischemia and hypoxia. ① Activated Drp1 induces mitochondrial calcium overload via MICU1/2, which disrupts the MCU channel. ② Drp1-induced mitochondrial calcium overload reduces mitochondrial membrane potential (ΔΨm) by promoting Na⁺-Ca²⁺ and Na⁺-H⁺ exchange at the IMM. ③ Drp1-induced mitochondrial calcium overload disrupts the TCA cycle and oxidative phosphorylation by affecting PDH activity, resulting in decreased ATP production and increased consumption. ④ “Circadian clock” effect of Drp1-Ser637 phosphorylation influences rhythmic mitochondrial bioenergetics, which may be related to the transcription-enzymatic interplay of rhythm genes Bmal1/Clock, and Drp1. Drp1 Dynamin-related protein 1, IMM inner mitochondrial membrane, TCA tricarboxylic acid, PDH pyruvate dehydrogenase, MCU mitochondrial calcium uniporter, MICU1 mitochondrial calcium uptake 1, RaM rapid Mode of mitochondrial calcium uptake, mRyR mitochondrial ryanodine receptor, ADP adenosine diphosphate, Pi inorganic phosphate, ATP adenosine triphosphate, NCX sodium-calcium exchanger, mPTP mitochondrial permeability transition pore, Per period, Cry cryptochrome, ROS reactive oxygen species, OCR oxygen consumption rate, UDP uridine diphosphate, GSH glutathione, GSSG glutathione disulfide