Work

The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness

Year: 2025

Type: article

Abstract: ABSTRACT The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX 3 C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103884

Authors: Christine Zarges, Hanna Fieler, Robin Alexander Rothemann, Simon Poepsel, Lucas T. Jae, Jan Riemer

Institutions: University of Cologne, Ludwig-Maximilians-Universität München, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne

Language: English

Topic: Mitochondrial Function and Pathology

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,310