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, 19 (8), 569-577

Tying Trafficking to Fusion and Fission at the Mighty Mitochondria


Tying Trafficking to Fusion and Fission at the Mighty Mitochondria

Trey Farmer et al. Traffic.


The mitochondrion is a unique organelle that serves as the main site of ATP generation needed for energy in the cell. However, mitochondria also play essential roles in cell death through apoptosis and necrosis, as well as a variety of crucial functions related to stress regulation, autophagy, lipid synthesis and calcium storage. There is a growing appreciation that mitochondrial function is regulated by the dynamics of its membrane fusion and fission; longer, fused mitochondria are optimal for ATP generation, whereas fission of mitochondria facilitates mitophagy and cell division. Despite the significance of mitochondrial homeostasis for such crucial cellular events, the intricate regulation of mitochondrial fusion and fission is only partially understood. Until very recently, only a single mitochondrial fission protein had been identified. Moreover, only now have researchers turned to address the upstream machinery that regulates mitochondrial fusion and fission proteins. Herein, we review the known GTPases involved in mitochondrial fusion and fission, but also highlight recent studies that address the mechanisms by which these GTPases are regulated. In particular, we draw attention to a substantial new body of literature linking endocytic regulatory proteins, such as the retromer VPS35 cargo selection complex subunit, to mitochondrial homeostasis. These recent studies suggest that relationships and cross-regulation between endocytic and mitochondrial pathways may be more widespread than previously assumed.

Keywords: Eps15 homology domain-containing protein 1; Mitofusin-1; Mitofusin-2; Rabankyrin-5; dynamin-related protein-1; dynamin2; fission; fusion; homeostasis; mitochondria; optic atrophy protein 1; retromer; vacuole protein sorting 35.


Figure 1
Figure 1. Mitochondrial Fusion
Mitochondria fusion via homotypic and heterotypic mitofusin interactions mediates OMM fusion, while OPA1 is responsible for IMM fusion events.
Figure 2
Figure 2. Mitochondrial Fission
Constriction of the mitochondrial membrane is first initiated by the ER at ER/mitochondria contact sites. After constriction by the ER, the mitochondrial membrane is “marked” for fission, thus resulting in Drp1 recruitment by Drp1 receptors. Drp1 then forms oligomers around the constriction site and further constricts the membrane through GTPase activity, leading to Dyn2/Dnm2 recruitment, additional GTP hydrolysis, and completion of the process of fission resulting in two separate mitochondria.
Fig. 3
Fig. 3. Potential roles of VPS35 in mitochondrial fission/fusion
Model representing the role of VPS35 (pink) in mitochondrial fission (bottom left) or mitochondrial fusion (top right). For fission, VPS35 removes inactive Drp1 (red) and traffics it to the lysosome for degradation, to allow active Drp1 (green) to further constrict the OMM. For fusion, VPS35 regulates MUL1 (orange) localization to the OMM, where it binds to Mfn2 (red) and induces its polyubiquitination (yellow) to target it for proteasomal degradation.

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