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Abstract Mitochondria play a crucial role in the regulation of cellular metabolism and signalling. Mitochondrial activity is modulated by the processes of mitochondrial fission and fusion, which are required to properly balance respiratory and metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at sites of contact between the endoplasmic reticulum (ER) and mitochondria, and is dependent on the formation of actin filaments that drive mitochondrial constriction and the recruitment and activation of the dynamin-related GTPase fission protein DRP1. The requirement for mitochondria- and ER-associated actin filaments in mitochondrial fission remains unclear, and the role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing the formation of actin filaments on either mitochondria or the ER disrupts both mitochondrial fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion are dependent on INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the dynamin family GTPase fusion protein MFN2. Together, our work introduces a novel method for perturbing organelle-associated actin filaments, and demonstrates a previously unknown role for actin in mitochondrial fusion.
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Optimizing mitochondrial maintenance in extended neuronal projections
Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mitochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, a key aspect underlying many neurodegenerative disorders.
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- Award ID(s):
- 1848057
- PAR ID:
- 10252373
- Editor(s):
- Beard, D
- Date Published:
- Journal Name:
- PLoS computational biology
- Volume:
- 17
- Issue:
- 6
- ISSN:
- 1553-7358
- Page Range / eLocation ID:
- e1009073
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/1009073
