Under normal conditions, free-state Drp1 molecules are located in the cytoplasm. However, the relationship between morphological and functional changes in the mitochondria following hypoxia has not been fully elucidated.ĭynamin-related protein 1 (Drp1), as a mitochondrial fission-associated GTPase, is a classical protein affecting mitochondrial morphological changes. This mainly manifested as abnormal mitochondrial morphology (such as excessive fission, impaired fusion, etc.) and mitochondrial dysfunction (such as decreased ATP production, excessive ROS accumulation, etc.), which promoted organ dysfunction after hypoxia. In our previous study, we found significant mitochondrial damage in tissues and organs, such as vascular, intestines, and the heart, after hypoxic injury. The mitochondrion, as the main site of aerobic respiration in cells, is one of the organelles that undergo damage immediately after ischemia and hypoxia. Severe hypoxic injury can cause organ dysfunction and may be life-threatening. It is a common pathway for the initiation and development of various critical illnesses, such as hemorrhagic shock, sepsis, and cardiopulmonary failure. Hypoxic injury refers to tissue cell injury caused by insufficient blood perfusion and blood oxygen supply. Thus, our study interprets the dual direct regulation of mitochondrial Drp1 on mitochondrial morphology and functions after hypoxia and proposes a new mitochondrial fission-independent mechanism for the role of Drp1 after its translocation in hypoxic injury. Subsequently, the mPTP-related protein hexokinase 2 (HK2) is inactivated at Thr-473 and dissociates from the mitochondrial membrane, ultimately causing structural disruption and overopening of mPTP, which aggravates mitochondrial and cellular dysfunction after hypoxia. Then, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is recruited, whose kinase activity is inhibited by direct binding with mitochondrial Drp1 after hypoxia.

Firstly, mitochondrial Drp1 maximumly recognizes mPTP channels by binding Bcl-2-associated X protein (BAX) and a phosphate carrier protein (PiC) in the mPTP. In this study, we performed a series of interaction and colocalization assays and found that, after mitochondrial translocation, Drp1 may promote the excessive opening of the mitochondrial permeability transition pore (mPTP) after hypoxia. However, in addition to mediating mitochondrial fission, whether Drp1 has other regulatory roles in mitochondrial homeostasis after mitochondrial translocation is unknown. The activation of dynamin-related protein 1 (Drp1), as well as its mitochondrial translocation, play important roles in the changes of both mitochondrial morphology and mitochondrial functions after hypoxia. Mitochondrial mass imbalance is one of the key causes of cardiovascular dysfunction after hypoxia.

Drp1 fission