bims-mitpro 2025-10-19 papers

Issue of 2025–10–19
two papers selected by
Andreas Kohler, Umeå University

Mol Cell Biol. 2025 Oct 17. 1-27

From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.

Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.

Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.

Keywords: Mitochondria; mitochondrial disease; protein import; protein quality control

DOI: https://doi.org/10.1080/10985549.2025.2566671

Biochem J. 2025 Oct 10. pii: BCJ20243016. [Epub ahead of print]

Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.

Yerranna Boggula, Arpan Chatterjee, Gaurav Simaiya, Amita Pal, Akash Srinivasan, Naresh Babu Sepuri.

Mitochondrial protein homeostasis depends mainly on the efficient import and folding of nuclear-encoded proteins, and defects in this process can lead to proteotoxicity, which is harmful to the cell. Mitochondrial chaperones and proteases are essential defense mechanisms that ensure dysfunctional proteins' proper concentration, folding, and degradation. Lon protease 1 (Pim1 in yeast) is the mitochondrial matrix protease known to prevent protein aggregation by degrading unfolded proteins. Here, we show that two essential components of ATP-dependent presequence translocase and associated motor (PAM complex)- Pam18 and Pam16 are specifically targeted for degradation by the proteolytically active Lon/Pim1, both in vitro and in vivo. Further, overexpression of Pam18 and Pam16 exacerbates the growth defect of the delta pim1 strain. Hence, our study reveals, for the first time, that components involved in protein import are substrates of Pim1, which could have potential implications for regulating mitochondrial protein import and proteostasis.

Keywords: Lon/Pim1 protease; Mitochondria; Protein turnover; Proteolysis; Proteostasis; Saccharomyces cerevisiae; mitochondrial protein import; presequence translocase-associated motor

DOI: https://doi.org/10.1042/BCJ20243016