Too Much Mitochondrial Fission in the Aging Germline Stem Cells of Flies

Mitochondria are bacteria-like organelles responsible for producing chemical energy store molecules to power cellular processes. Hundreds of them exist in every cell, constantly undergoing fusion and fission, swapping component parts with one another, and being culled when damaged by the quality control mechanism of mitophagy. Past work has indicated that there is too little mitochondrial fission in old cells, leading to mitochondria that are too large to be effectively removed when damaged. The research here suggests that there is instead too much mitochondrial fission in stem cells, though it is focused specifically on germline stem cells in flies. Mitochondrial dynamics is a balance, and disruption in either direction is problematic. Age-related disruption may well be different in different species and cell types, so it is a little early to say whether or not the work here is relevant to mammals.

Mitochondria frequently undergo coordinated cycles of fusion and fission (known as mitochondrial dynamics) to properly adjust the shape, size, and cellular distribution of the organelle to meet specific cellular requirements. Fusion produces elongated mitochondria by respectively joining the outer and inner membranes of two mitochondria. The closely related Dynamin-related GTPases, Mfn1 and Mfn2, mediate outer membrane fusion, while Opa1 is integral for fusion of the inner membrane. On the other hand, excessive mitochondrial fission produces fragmented mitochondria and is mediated by another Dynamin-related GTPase, called Drp1. Drp1 is recruited by its receptors on the outer membrane and oligomerizes along the mitochondrial constriction site to constrict the organelle and induce scission.

Mitochondrial dynamics are known to influence several mitochondria-dependent biological processes, such as lipid homeostasis, calcium homeostasis, and ATP production. Recent studies have also proposed a role for mitochondrial fusion and fission in regulating stem cell fate. In one interesting example, murine neural stem cells were shown to exhibit elongated mitochondria, and depletion of Mfn1 or Opa1 impaired their self-renewal. Despite tantalizing observations such as these, the overall impact of mitochondrial dynamics in aging stem cells and the mechanisms by which mitochondrial dynamics might affect stem cell function remain unclear.

Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging-related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator Drp1 are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition.

Link: https://doi.org/10.1111/acel.13191

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