Abstract
The mitochondrial intermembrane space (IMS) is the most constricted sub-mitochondrial compartment, housing only about 5% of the mitochondrial proteome, and yet is endowed with the largest variability of protein import mechanisms. In this review, we summarize our current knowledge of the major IMS import pathway based on the oxidative protein folding pathway and discuss the stunning variability of other IMS protein import pathways. As IMS-localized proteins only have to cross the outer mitochondrial membrane, they do not require energy sources like ATP hydrolysis in the mitochondrial matrix or the inner membrane electrochemical potential which are critical for import into the matrix or insertion into the inner membrane. We also explore several atypical IMS import pathways that are still not very well understood and are guided by poorly defined or completely unknown targeting peptides. Importantly, many of the IMS proteins are linked to several human diseases, and it is therefore crucial to understand how they reach their normal site of function in the IMS. In the final part of this review, we discuss current understanding of how such IMS protein underpin a large spectrum of human disorders.
Highlights
The mitochondrion is a relatively small yet complex organelle responsible for a plethora of cellular activities, the production of 95% of the cell’s ATP being just one of them
The intermembrane space (IMS) is the smallest of the two aqueous sub-compartments, but it is responsible for several of the aforementioned functions within mitochondria. 99% of the proteins that reside in mitochondria are nuclear-encoded and have to be imported into the organelle via different protein translocases and import complexes that direct each protein to the correct compartment
The difference in the annotation of 127 proteins as human IMS proteins in MitoCarta 2.0 [2] arises from (i) the fact that IMS-APEX2 proximity biotinylation used in [3] labels IMS as well as these in the mitochondrial OM and IM that are accessible to the IMS biotin label, and (ii) the fact that some proteins that are in the IMS during their biogenesis have been annotated in [4] as IM proteins if they mature to be part of a complex in the IM
Summary
The mitochondrion is a relatively small yet complex organelle responsible for a plethora of cellular activities, the production of 95% of the cell’s ATP being just one of them. The IMS is the smallest of the two aqueous sub-compartments (the other one being the innermost matrix of mitochondria), but it is responsible for several of the aforementioned functions within mitochondria. 99% of the proteins that reside in mitochondria are nuclear-encoded and have to be imported into the organelle via different protein translocases and import complexes that direct each protein to the correct compartment. We discuss each of the several IMS import pathways including the Mia, cytochrome b2, cytochrome c, cytochrome c haem lyase (CCHL) and UCP import pathways. The IMS contains many rather small but structurally distinct proteins that are implicated in several human diseases including several mitochondriopathies, amyotrophic lateral sclerosis (ALS), Parkinson’s disease and Alzheimer’s disease (AS). The roles of dysfunctional mitochondrial IMS proteins in underpinning these diseases are discussed in this review
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
