Apart from 13 core subunits of the OXPHOS pathway, all the human mitochondrial proteome is encoded by the nuclear genome. Following synthesis on cytosolic ribosomes, proteins for mitochondrial function are thus imported to that organelle from the cytosol as unfolded precursor polypeptides, a consequence of limited pore size of the import machinery. Only then do they undergo tertiary structural folding to avoid aggregation within the mitochondrion.
Mitochondrial HSP70 (mtHSP70) is a highly conserved chaperone system critical in facilitating mitochondrial protein biogenesis, with two important functions:
- alone, in mitochondrial precursor import via ATP hydrolysis, and
- as part of a chaperone complex, in folding of newly imported polypeptides into their native structures
Another mitochondrial protein with potential chaperone function is LONP1, an ATPase & protease of the mitochondrial matrix, but this function & its molecular basis has not previously been well-defined, and never directly demonstrated on a specific substrate.
In this study, Shin et al investigate the role and mechanism of action of LONP1 in the mtHSP70 chaperone complex, demonstrating that it also plays a major role in mitochondrial protein biogenesis. They show it is the ATPase, not the protease activity of LONP1 that regulates the solubility of mtHSP70 and co-chaperones in this pathway. In the absence of LONP1, the authors suggest that mtHSP70 engages in futile folding interactions with mitochondrial precursors, leading to co-aggregation with substrates. In this regard, they utilised LC-MS mass spectrometry with IonOpticks Aurora Series columns to analyse mitochondrial protein aggregates, and identified 29 specific subunits of the OXPHOS pathway complexes as substrates that became significantly insoluble upon LONP1 inhibition.
The authors conclude that LONP1 and mtHSP70 likely work together to facilitate folding much of the mitochondrial proteome, and hence why syndromes such as CODAS & EVEN-PLUS share such similar symptoms.
Read the full paper
LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding.
Nature Communications. 12, 265, 11 Jan 2021. doi: https://doi.org/10.1038/s41467-020-20597-z
Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick & David C. Chan.
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.