The ever-growing complexity of the mitochondrial fission machinery

Abstract

The mitochondrial network constantly changes and remodels its shape to face the cellular energy demand. In human cells, mitochondrial fusion is regulated by the large, evolutionarily conserved GTPases Mfn1 and Mfn2, which are embedded in the mitochondrial outer membrane, and by OPA1, embedded in the mitochondrial inner membrane. In contrast, the soluble dynamin-related GTPase Drp1 is recruited from the cytosol to mitochondria and is key to mitochondrial fission. A number of new players have been recently involved in Drp1-dependent mitochondrial fission, ranging from large cellular structures such as the ER and the cytoskeleton to the surprising involvement of the endocytic dynamin 2 in the terminal abscission step. Here we review the recent findings that have expanded the mechanistic model for the mitochondrial fission process in human cells and highlight open questions.

Keywords: Actin; Cytoskeleton; Drp1; Dyn2; Dynamin; ER; Mitochondrial dynamics; Mitochondrial fusion; Nucleoid; Septin; mtDNA.

Fig. 1

Mitochondrial fusion and fission. a Mitochondria tethering via homotypic (Mfn1–Mfn1 and Mfn2–Mfn2) and heterotypic (Mfn1–Mfn2) mitofusin interactions promotes OMM fusion, while inner membrane fusion is promoted by OPA1. b Schematic representation of mitochondrial fission. Enlargements of OMM and IMM fusion events that occur during mitochondrial fusion and fission. c Immunofluorescence showing changes in mitochondrial morphology (red) and Drp1 localization (green) in response to different perturbations. Adapted from [182, 190, 202]

Fig. 2

Domain structure of Drp1, its modifications and receptors. a The family of mitochondrial dynamics proteins and their bacterial ancestor, the bacterial dynamin-like protein BDLP. Abbreviations: paddle domain (PAD) and pleckstrin homology domain (PH), both responsible for lipid binding; proline-rich domain (PRD), tetratricopeptide (TPR) and coiled–coiled (CC) domains are involved in protein–protein interactions; GTPase effector domain (GED); insert B domain (Ins B); transmembrane domain (TM). b full-length human Drp1 (isoform 1, 736 aa). Numbers indicate the start of a new domain. Posttranslational modifications are colour-coded, and the modified amino acids have been indicated, except for ubiquitination and O-GlcNAcylation (grey), for which sites have not yet been identified. A few commonly used mutants are shown in black: K38A (dominant-negative), G350D (impaired in higher order oligomerization), A395D (natural mutation, impaired in tetramerization and higher order oligomerization). c Drp1 is recruited to the OMM via multiple transmembrane receptors. MiD51 and Mff are able to oligomerize and to interact with each other in the same fission foci. The SAMM50 protein has been shown to interact with the MITOS complex in the IMM

Fig. 3

The cytoskeleton contributes to Drp1-dependent mitochondrial fission. a Linear actin polymerized by INF2 and Spire1C at the ER–mitochondria contact sites contributes to mitochondrial constriction with the aid of Myosin II, promoting Drp1 recruitment and mitochondrial fission. b Arp2/3 complex-mediated polymerization of branched actin on the OMM regulates Drp1 dynamics and mitochondrial fission. c Septins interact with Drp1 to regulate Drp1-mediated mitochondrial fission

Fig. 4

Mitochondrial fission is a multistep process. a The site of fission on mitochondria is first marked by an ER tubule which constricts mitochondria by wrapping around them. b Drp1 is recruited to the OMM with the aid of receptors, actin and septins, oligomerizes and initiates mitochondrial constriction. c Dynamin is recruited through an unknown mechanism and d drives mitochondrial abscission upon GTP hydrolysis