A mitochondrial delicacy: dynamin-related protein 1 and mitochondrial dynamics

Abstract

The constant physiological flux of mitochondrial fission and fusion is inextricably tied to the maintenance of cellular bioenergetics and the fluidity of mitochondrial networks. Yet, the intricacies of this dynamic duo remain unclear in diseases that encompass mitochondrial dysregulation. Particularly, the role of the GTPase fission protein dynamin-related protein 1 (Drp1) is of profound interest. Studies have identified that Drp1 participates in complex signaling pathways, suggesting that the function of mitochondria in pathophysiology may extend far beyond energetics alone. Research indicates that, in stressed conditions, Drp1 translocation to the mitochondria leads to elevated fragmentation and mitophagy; however, despite this, there is limited knowledge about the mechanistic regulation of Drp1 in disease conditions. This review highlights literature about fission, fusion, and, more importantly, discusses Drp1 in cardiac, neural, carcinogenic, renal, and pulmonary diseases. The therapeutic desirability for further research into its contribution to diseases that involve mitochondrial dysregulation is also discussed.

Keywords: Drp1 modulation; dynamin-related protein 1, mitochondrial fission and fusion, mitophagy.

Fig. 1.

Dynamin-related protein 1 (Drp1) and mitochondrial fission. Drp1 can be targeted to a marked mitochondrion by phosphorylation on specific serine residues (see Fig. 2). From there, fission protein 1 (Fis1), mitochondrial fission factor (Mff), and mitochondrial elongation factor proteins of 49 and 51 kDa (MiD49/51) play a role in directing Drp1 to the fission site to form a spiral multimer around the mitochondrion (not depicted fully). Meanwhile, the mitochondrion is encircled by the endoplasmic reticulum (ER). Actin filaments polymerize between Spire1C (suggested), a mitochondrial membrane protein, and inverted formin 2 (INF2), a membrane-bound protein on the ER. These actin filaments guide an initial constriction event, which then permits complete fission via Drp1 GTPase activity (GTP → GDP + inorganic phosphate). Notably, mitochondrial fission can release cytochrome c through Bax/Bak membrane pores and trigger formation of the apoptosome. Direct stimulation of Bad inhibits Bcl-1 and halts the inhibition of Bax. Upon translocation to the mitochondria, Bax colocalizes with Drp1. Pink1, PTEN-induced kinase 1.

Fig. 2.

Phosphorylation control points and domains of dynamin-related protein 1 (Drp1). The Drp1 protein has five notable domains and several points of regulation. The domains are as follows: GTPase, middle, glycogen synthase kinase 3β (GSK3β) interaction, B, and GTPase effector domain (GED). Bars below the domain sequence denote a continuation of the section and provide a visual representation of overlapping domains.

Fig. 3.

Inhibitors of dynamin-related protein 1 (Drp1). P110 is a Drp1-specific inhibitor that binds directly to Drp1. In some cases, this binding inhibits translocation to the mitochondria or prevents mitochondrial docking. In other cases, P110 prevents Drp1 oligomerization. Similarly, established literature reports that Mdivi-1 also prevents translocation and multimer formation of Drp1. A 2017 study provided evidence that Mdivi-1 bypasses mitochondrial fission machinery and instead inhibits Complex I of the electron transport chain (5).