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The small GTPase Arf1 modulates mitochondrial morphology and function
Karin B Ackema1, Jürgen Hench2, Stefan Böckler3
1Growth and Development, Biozentrum University of Basel, Basel, Switzerland.
Abstract:
The small GTPase Arf1 plays critical roles in membrane traffic by initiating the recruitment of coat proteins and by modulating the activity of lipid-modifying enzymes. Here, we report an unexpected but evolutionarily conserved role for Arf1 and the ArfGEF GBF1 at mitochondria. Loss of function of ARF-1 or GBF-1 impaired mitochondrial morphology and activity in Caenorhabditis elegans. Similarly, mitochondrial defects were observed in mammalian and yeast cells. In Saccharomyces cerevisiae, aberrant clusters of the mitofusin Fzo1 accumulated in arf1-11 mutants and were resolved by overexpression of Cdc48, an AAA-ATPase involved in ER and mitochondria-associated degradation processes. Yeast Arf1 co-fractionated with ER and mitochondrial membranes and interacted genetically with the contact site component Gem1. Furthermore, similar mitochondrial abnormalities resulted from knockdown of either GBF-1 or contact site components in worms, suggesting that the role of Arf1 in mitochondrial functioning is linked to ER-mitochondrial contacts. Thus, Arf1 is involved in mitochondrial homeostasis and dynamics, independent of its role in vesicular traffic.
Insights
The small GTPase Arf1 and GBF1 are crucial for mitochondrial health, impacting morphology and activity across species. This function is linked to ER-mitochondrial contacts, independent of Arf1
Area of Science:
- Cell Biology
- Molecular Biology
- Mitochondrial Biology
Background:
- The small GTPase Arf1 is known for its role in membrane traffic and protein coat recruitment.
- Its involvement in other cellular processes beyond vesicular transport remains largely unexplored.
Purpose of the Study:
- To investigate the potential role of Arf1 and its associated guanine nucleotide exchange factor (GBF1) in mitochondrial function.
- To determine if Arf1's mitochondrial role is conserved across different species and linked to specific cellular structures.
Main Methods:
- Utilized loss-of-function mutants in *Caenorhabditis elegans* and *Saccharomyces cerevisiae* to assess mitochondrial morphology and activity.
- Performed co-fractionation studies to examine the localization of yeast Arf1.
- Investigated genetic interactions between Arf1 and components of ER-mitochondrial contact sites.
Main Results:
- Loss of Arf1 or GBF1 function led to impaired mitochondrial morphology and activity in *C. elegans*, mammalian cells, and yeast.
- In yeast, Arf1 mutants showed accumulation of the mitofusin Fzo1, which was rescued by Cdc48 overexpression.
- Yeast Arf1 was found to co-fractionate with ER and mitochondrial membranes and genetically interact with Gem1, a contact site component.
Conclusions:
- Arf1 and GBF1 play a conserved, unexpected role in maintaining mitochondrial homeostasis and dynamics.
- This mitochondrial function of Arf1 is associated with ER-mitochondrial contacts and is independent of its canonical role in vesicular traffic.
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