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Published on: January 11, 2017
Interaction with the effector dynamin-related protein 1 (Drp1) is an ancient function of Rab32 subfamily proteins
Carolina G Ortiz-Sandoval1, Sarah C Hughes2, Joel B Dacks1
1Faculty of Medicine and Dentistry; Department of Cell Biology; University of Alberta ; Edmonton, Alberta, Canada.
Abstract:
The mitochondria-associated membrane (MAM) is an endoplasmic reticulum (ER) domain that forms contacts with mitochondria and accommodates Ca2+ transfer between the two organelles. The GTPase Rab32 regulates this function of the MAM via determining the localization of the Ca2+ regulatory transmembrane protein calnexin to the MAM. Another function of the MAM is the regulation of mitochondrial dynamics mediated by GTPases such as dynamin-related protein 1 (Drp1). Consistent with the importance of the MAM for mitochondrial dynamics and the role of Rab32 in MAM enrichment, the inactivation of Rab32 leads to mitochondrial collapse around the nucleus. However, Rab32 and related Rabs also perform intracellular functions at locations other than the MAM including melanosomal trafficking, autophagosome formation and maturation, and retrograde trafficking to the trans-Golgi network (TGN). This plethora of functions raises questions concerning the original cellular role of Rab32 in the last common ancestor of animals and its possible role in the last eukaryotic common ancestor (LECA). Our results now shed light on this conundrum and identify a role in Drp1-mediated mitochondrial dynamics as one common denominator of this group of Rabs, which includes the paralogues Rab32A and Rab32B, as well as the more recently derived Rab29 and Rab38 proteins. Moreover, we provide evidence that this mitochondrial function is dictated by the extent of ER-association of Rab32 family proteins.
Insights
Rab32 GTPase family proteins regulate mitochondrial dynamics by interacting with the endoplasmic reticulum. This ER-association is key to their function in maintaining mitochondrial health and dynamics.
Area of Science:
- Cell Biology
- Mitochondrial Dynamics
- Endoplasmic Reticulum Function
Background:
- Mitochondria-associated membranes (MAM) are ER domains crucial for inter-organelle communication, including calcium transfer.
- The GTPase Rab32 localizes calnexin to the MAM and influences mitochondrial dynamics, with its inactivation causing mitochondrial collapse.
- Rab32 family proteins have diverse roles, including melanosomal trafficking and autophagosome maturation, prompting investigation into their ancestral functions.
Purpose of the Study:
- To elucidate the ancestral cellular role of Rab32 and related GTPases.
- To identify a common function linking Rab32 family proteins across different cellular locations.
- To investigate the role of ER-association in Rab32-mediated mitochondrial function.
Main Methods:
- Analysis of Rab32 family proteins (Rab32A, Rab32B, Rab29, Rab38) and their paralogues.
- Investigation of Rab GTPase involvement in dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics.
- Assessment of the correlation between ER-association of Rab32 family proteins and their mitochondrial function.
Main Results:
- A conserved role in Drp1-mediated mitochondrial dynamics was identified for the Rab32 GTPase family.
- This mitochondrial function appears to be a common denominator for Rab32, Rab32A, Rab32B, Rab29, and Rab38.
- The extent of ER-association of Rab32 family proteins dictates their mitochondrial function.
Conclusions:
- Rab32 family proteins play a fundamental role in regulating mitochondrial dynamics.
- ER-association is a critical determinant of Rab32's function in mitochondrial health.
- This study sheds light on the evolutionary conserved role of Rab GTPases in mitochondrial regulation.
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