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bioRxiv · 10.1101/2024.02.07.579360

Developmental disruption of the mitochondrial fissiongene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant

Traa, A.·Van Raamsdonk, J.
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Abstract

The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cells ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. While disruption of the mitochondrial fission gene drp-1 only mildly increases wild-type lifespan, it drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with a number of different RNAi clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses and slows physiologic rates in daf-2 worms. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels or mitochondrial membrane potential. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

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Traa, A., Van Raamsdonk, J.. 2024-02-08. Developmental disruption of the mitochondrial fissiongene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant. https://doi.org/10.1101/2024.02.07.579360

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