Dataset Information

The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space.

ABSTRACT: Mitochondria are essential, dynamic organelles that regularly undergo both fusion and fission in response to cellular conditions, though mechanisms of the regulation of their dynamics are incompletely understood. We provide evidence that increased activity of the small GTPase ARL2 is strongly correlated with an increase in fusion, while loss of ARL2 activity results in a decreased rate of mitochondrial fusion. Strikingly, expression of activated ARL2 can partially restore the loss of fusion resulting from deletion of either mitofusin 1 (MFN1) or mitofusin 2 (MFN2), but not deletion of both. We only observe the full effects of ARL2 on mitochondrial fusion when it is present in the intermembrane space (IMS), as constructs driven to the matrix or prevented from entering mitochondria are essentially inactive in promoting fusion. Thus, ARL2 is the first regulatory (small) GTPase shown to act inside mitochondria or in the fusion pathway. Finally, using high-resolution, structured illumination microscopy (SIM), we find that ARL2 and mitofusin immunoreactivities present as punctate staining along mitochondria that share a spatial convergence in fluorescence signals. Thus, we propose that ARL2 plays a regulatory role in mitochondrial fusion, acting from the IMS and requiring at least one of the mitofusins in their canonical role in fusion of the outer membranes.

SUBMITTER: Newman LE

PROVIDER: S-EPMC5602422 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space.

Newman Laura E LE Schiavon Cara R CR Turn Rachel E RE Kahn Richard A RA

Cellular logistics 20170623 3

Mitochondria are essential, dynamic organelles that regularly undergo both fusion and fission in response to cellular conditions, though mechanisms of the regulation of their dynamics are incompletely understood. We provide evidence that increased activity of the small GTPase ARL2 is strongly correlated with an increase in fusion, while loss of ARL2 activity results in a decreased rate of mitochondrial fusion. Strikingly, expression of activated ARL2 can partially restore the loss of fusion resu ...[more]

PMID: 28944094

Similar Datasets

Project description:BACKGROUND:The proteome of mitochondria comprises mostly proteins that originate as precursors in the cytosol. Before import into the organelle, such proteins are exposed to cytosolic quality control mechanisms. Multiple lines of evidence indicate a significant contribution of the major cytosolic protein degradation machinery, the ubiquitin-proteasome system, to the quality control of mitochondrial proteins. Proteins that are directed to the mitochondrial intermembrane space (IMS) exemplify an entire class of mitochondrial proteins regulated by proteasomal degradation. However, little is known about how these proteins are selected for degradation. RESULTS:The present study revealed the heterogeneous cytosolic stability of IMS proteins. Using a screening approach, we found that different cytosolic factors are responsible for the degradation of specific IMS proteins, with no single common factor involved in the degradation of all IMS proteins. We found that the Cox12 protein is rapidly degraded when localized to the cytosol, thus providing a sensitive experimental model. Using Cox12, we found that lysine residues but not conserved cysteine residues are among the degron features important for protein ubiquitination. We observed the redundancy of ubiquitination components, with significant roles of Ubc4 E2 ubiquitin-conjugating enzyme and Rsp5 E3 ubiquitin ligase. The amount of ubiquitinated Cox12 was inversely related to mitochondrial import efficiency. Importantly, we found that precursor protein ubiquitination blocks its import into mitochondria. CONCLUSIONS:The present study confirms the involvement of ubiquitin-proteasome system in the quality control of mitochondrial IMS proteins in the cytosol. Notably, ubiquitination of IMS proteins prohibits their import into mitochondria. Therefore, ubiquitination directly affects the availability of precursor proteins for organelle biogenesis. Importantly, despite their structural similarities, IMS proteins are not selected for degradation in a uniform way. Instead, specific IMS proteins rely on discrete components of the ubiquitination machinery to mediate their clearance by the proteasome.

Dataset Information

The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space.

Publications

The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets