Editors' ChoiceCell Biology

Leaving the damage behind

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Science Signaling  22 Jun 2021:
Vol. 14, Issue 688, eabj6781
DOI: 10.1126/scisignal.abj6781

A mechanism by which migrating cells shed defective mitochondria is identified.

Mitochondria are eliminated by various mechanisms when they do not meet quality control standards. Jiao et al. characterized a mechanism they called mitocytosis by which damaged mitochondria are shed by migrating cells in vesicle-like organelles called migrasomes (see also the commentary by Green). Migrasomes form on retraction fibers, which are plasma membrane extensions at the rear of migrating cells, in a manner dependent on tetraspanins 4 and 9 (TSPAN4 and TSPAN9). Migrasomes are left behind when retraction fibers break as cells move. The authors found that the induction of mitochondrial stress in L929 cells, such as by treatment with the oxidative phosphorylation uncoupler CCCP or by starvation, resulted in the presence of mitochondria with signs of damage in migrasomes. These mitochondria were located primarily in the layer of cells closest to the substrate. Mitocytosis required the anterograde motor protein KIF5B, the mitochondrion-associated myosin isoform Myosin19, and the mitochondrial fission factor Drp1. Mitochondria that underwent mitocytosis had low mitochondrial membrane potential (MMP), high concentrations of ROS, and mutations in mitochondrial DNA, and showed reduced binding to the minus end–directed microtubule motor protein dynein. Increasing mitocytosis by overexpressing TSPAN4 or knocking down dynein enabled L929 cells to recover more quickly after CCCP treatment and increased the spare respiratory capacity of mitochondria. In mice deficient in TSPAN9, MMP was reduced in bone marrow–derived macrophages or neutrophils, but not in hepatocytes (which are immobile, unlike macrophages or neutrophils), and neutrophils from the spleens of these mice had decreased viability. These results identify mitocytosis as a mechanism for disposing of defective mitochondria that is specific to migrating cells.

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