ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.

Authors

Julia Racho, Dylan Stobbe, Jan Jirschitzka, Marijana Croon, Carmelina Petrungaro, Muna Ali, Dario Wernet, Markus Habich, Nele Sophie Gawellek, Julian Strippel, Finn Dicke, Jörn Dengjel, Stephanie Kath-Schorr, Bent Brachvogel, Thomas Langer, Aleksandra Trifunovic, Ines Neundorf, Jan Riemer

Published in

Science advances. Volume 12. Issue 29. Pages eaed2430. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

Proteins in the mitochondrial intermembrane space (IMS) play essential roles in respiratory chain assembly, metabolism, signaling, and organelle dynamics. Their stability and functionality often depend on structural disulfide bonds introduced by the mitochondrial disulfide relay, mediated by MIA40 and ALR. In this system, the sulfhydryl oxidase ALR reoxidizes MIA40, which in turn oxidizes incoming substrate proteins. Although evidence has suggested that ALR can also act independently of MIA40, its endogenous substrates have remained unknown. In this study, we captured proteins directly oxidized by ALR. Among these, we found coproporphyrinogen III oxidase (CPOX), a key enzyme in heme biosynthesis. We show that ALR-mediated disulfide bond formation is crucial for maintaining CPOX stability in the IMS, thereby ensuring effective heme biosynthesis and mitochondrial functionality. Notably, while disulfide-deficient CPOX failed to rescue CPOX loss when localized to the IMS, it retained functionality when redirected to the cytosol. However, this bypass compromised pathway efficiency, leading to the accumulation of protoporphyrinogen IX, a highly hydrophobic and redox-active intermediate that sensitized cells to cell death. Together, our findings reveal that ALR has functions beyond the MIA pathway and highlight that oxidative protein folding in the IMS relies not only on a relay mechanism but also on a broader disulfide-introducing network of enzymes.

PMID:
42467788
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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