Club bouncer: the ubiquitin system dynamically regulates mitochondrial import at the TOM complex.


Mitochondria import almost their entire proteome from the cytoplasm by translocating precursor proteins through the translocase of the outer membrane (TOM) complex, embedded in the mitochondrial surface.

The mitochondrial import process is highly orchestrated, regulated as it is by multiple mechanisms that couple organelle function to cellular metabolism and engaging cellular signalling networks to maintain mitochondrial and cellular fitness. When import is impaired, eg by a non-functioning TOM, some proteins intended for the mitochondria are instead redirected to the nucleus to induce a protective transcriptional program. Accumulation of unimported mitochondrial precursors also generates a cytosolic stress response, downregulating global protein synthesis. The TOM complex additionally functions both as a sensor of mitochondrial stress and mitochondrial damage, relaying biochemical signals to the cellular mitophagy machinery to degrade damaged mitochondria.

Import efficiency can be regulated bi-directionally by several mechanisms, including TOM receptor phosphorylation to promote or impair substrate recognition in response to nutrient availability and energy demands.

Through a series of CRISPR and inducible knockout experiments and using LC-MS/MS (including use of IonOpticks Aurora Series columns) to analyse the changes induced in the mitochondrial ubiquitylome, the authors demonstrate a dynamic regulation of mitochondrial import by the ubiquitin system.  This occurred through coordinated modification of substrates before and during the process of import, specifically by two enzymes tethered on the mitochondrial surface – the E3 ubiquitin ligase March5 and the deubiquitinase USP30, that reciprocally modify import substrates at the TOM complex.  The diverse array of proteins regulated by USP30, belonging to multiple functional classes, suggests a broad regulatory role for the ubiquitin system in mitochondrial import, with March5 functioning in a quality control pathway via ubiquitination of intramitochondrial substrates.

Read the full paper
Dynamic Regulation of Mitochondrial Import by the Ubiquitin System.
Molecular Cell. 77, 1107–1123 March 5, 2020. doi: https://doi.org/10.1016/j.molcel.2020.02.012

Lilian Phu, Christopher M. Rose Joy S. Tea, Christopher E. Wall, Erik Verschueren, Tommy K. Cheung, Donald S. Kirkpatrick, Baris Bingol.

Commentary by Muhammad Zenaidee, PhD

About the author
Muhammad holds a PhD in Chemistry from The University of New South Wales and has a strong background in the development of tools to enhance top-down and bottom-up proteomics. As an Application Scientist at IonOpticks, he utilises his knowledge and training to develop new proteomics tools and technologies for the proteomics community.