NOVEL TARGETS OF THE SULFHYDRYL : CYTOCHROME C OXIDOREDUCTASE ALR

• Applicant: Professor Dr. Jan Riemer
• Subject Area: Biochemistry
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435235019

Disulfide bond formation in the mitochondrial intermembrane space (IMS) is a critical process essential for establishing and maintaining protein structures, regulating protein functions, and driving enzyme reactions as part of various reaction cycles. In human cells, the mitochondrial disulfide relay system, comprising the core components ALR and MIA40, plays a pivotal role in catalyzing disulfide bond formation within the IMS. MIA40 is indispensable for the IMS import and oxidative folding of numerous substrate proteins, while ALR has traditionally been thought to primarily regenerate MIA40, ensuring its sustained activity. In this process, ALR accepts electrons from MIA40 and transfers them to cytochrome c in an electron relay reaction. We hypothesize that the role of human ALR extends beyond its conventional function as a regenerating enzyme for MIA40. Instead, we propose that ALR acts as a central electron relay hub in the IMS. Recent proteomic studies have revealed that ALR interacts with a broad spectrum of proteins, suggesting a more diverse functional repertoire. This project aims to explore whether ALR performs additional, previously unrecognized functions. Specifically, we will investigate the mechanistic, functional, and physiological implications of ALR-dependent oxidation on novel target proteins. Overall, this work will provide valuable insights into the mitochondrial disulfide relay machinery, the biology of the IMS, and the broader processes of oxidative protein folding.

• DFG Programme: Research Grants