The Mitochondria-Cytosol Fe-S Connection: Grx5 is the Traffic Controller
- Ray Sullivan
- 2 hours ago
- 2 min read
Iron-sulfur (Fe-S) clusters are essential molecular workhorses in our cells, powering processes from energy production to DNA repair. Their creation and distribution rely on two main cellular factories: the mitochondrial ISC (Iron-Sulfur Cluster) machinery and the cytoplasmic CIA (Cytoplasmic Iron-Sulfur Protein Assembly) machinery. These two systems are functionally linked, as mitochondria produce and export intermediates necessary for Fe-S cluster assembly in the rest of the cell.
A key component within the mitochondrial ISC machinery is Glutaredoxin 5 (Grx5). Glutaredoxins play a role in cellular redox homeostasis by catalyzing the transfer or formation of disulfide bonds using glutathione as a reducing agent. Grx5 is a type of glutaredoxin localized in mitochondria. It is highly conserved from yeast to humans. This deep conservation underscores its fundamental importance, and indeed, Grx5 deficiency or mutations in humans are linked to severe, often fatal diseases like sideroblastic anemia and spasticity with hyperglycinemia. These conditions often involve problems with cellular iron handling and defects in Fe-S enzyme function.
To understand exactly what Grx5 does, Debkumar Pain's Lab at Rutgers New Jersey Medical School used a powerful approach: studying isolated mitochondria and cytoplasm from yeast. This allowed them to examine Fe-S cluster assembly and trafficking steps in controlled environments. They specifically looked at yeast strains lacking Grx5 (Grx5↓) or other downstream ISC proteins like Isa1 or Isa2.
The studies confirmed that Grx5 is essential for mitochondrial Fe-S cluster formation. Mitochondria lacking Grx5 were severely defective in assembling [4Fe-4S] clusters on the enzyme aconitase. Crucially, importing purified Grx5 protein into Grx5↓ mitochondria restored their ability to assemble [4Fe-4S] clusters on aconitase.
Perhaps even more significantly, the research revealed Grx5's critical role in supporting the cytoplasm. Isolated cytoplasm cannot assemble Fe-S clusters on its own; it requires an intermediate (so called (Fe-S)int) exported from mitochondria. Using indicator proteins like DNYah1 (a cytoplasmic form of Yah1 that accepts a [2Fe-2S] cluster) and the enzyme Leu1 (which needs a [4Fe-4S] cluster), the researchers found that Grx5↓ mitochondria failed to promote Fe-S cluster assembly in isolated cytoplasm. They could not generate or export the necessary (Fe-S)int.
Importantly, while Grx5 was essential for this, downstream mitochondrial proteins like Isa1 and Isa2 were not required for generating or exporting the (Fe-S)int. This places Grx5 earlier in the pathway leading to cytoplasmic Fe-S assembly than the ISA complex.
Moreover, importing purified Grx5 into Grx5↓ mitochondria fully restored their ability to support Fe-S cluster assembly in the cytoplasm. This was shown by rescue of both DNYah1 labeling and Leu1 enzyme activation.
These findings lead to the conclusion that Grx5 acts as a "central hub" or "focal point" in mitochondria. It's needed for Fe-S cluster synthesis/trafficking within mitochondria and is uniquely required among downstream components for producing the (Fe-S)int that gets exported to fuel cytoplasmic Fe-S cluster assembly. Understanding this critical role of Grx5 provides vital insights into how Fe-S cluster defects arise and how they might lead to the devastating human diseases linked to Grx5 dysfunction.
Pandey AK, Pain J, Singh P, Dancis A, Pain D. Mitochondrial glutaredoxin Grx5 functions as a central hub for cellular iron-sulfur cluster assembly. J Biol Chem. 2025 Apr;301(4):108391. doi: 10.1016/j.jbc.2025.108391. Epub 2025 Mar 10. PMID: 40074084; PMCID: PMC12004709.