TABLE 1.
Proteins and metabolites key to the pathology of FRDA.
| Name | Gene symbol | Function | FRDA relevance |
| Aconitase | ACO2 | Citrate-isocitrate conversion in TCA cycle (mitochondrial), modulates IRE-containing gene transcription (cytoplasmic) | ISC containing, decreased activity in FXN deficiency |
| Cysteamine/Cystamine | Provides cysteine in glutathione synthesis | Anti-oxidant, potential rescue of glutathione metabolism in FXN deficiency | |
| F-actin | ACTB | Cytoskeleton formation, anchorage of junction proteins, anchorage of organelles | Lack of polymerization and tropomyosin binding in FXN deficiency. Gives cells altered morphology |
| Frataxin | FXN | Iron incorporation into ISCs and heme centers | Decreased transcription and protein production in FRDA Inefficient ISC and heme biosynthesis |
| Glutathione Effectors: Glutaredoxin (Grx) Glutathione-S-Transferase (GST) Sulfiredoxin (Sfx) Thioredoxin (Trx) Peroxiredoxin (Prx) | GLRX GSTP/M/A/T SRXN1 TXN PRDX1/2/6 | GSSG → (2)GSH GSH + HSP → GSSP S-S → (2)SH S-S → (2)SH S-S → (2)SH | FXN-deficiency promotes increased glutathionylation of proteins. Cell GSH buffering capacity depressed due to pathologic oxidative stress. Actin glutathionylation disrupts protein-protein interactions in actin polymerization and anchorage of tight junction proteins |
| ISD11 | LYRM4 | ISC scaffolding protein, functional interaction with FXN | A lack of FXN prevents efficient ISC cluster formation at the step of iron insertion |
| Keap1 | KEAP1 | Tethers Nrf2 proteins to actin bundles, preventing ARE-containing gene transcription | Loss of Keap1 binding to actin filaments in FRDA prevents tethering of Nrf2, preventing its activity as a transcription factor |
| Nrf2 | NFE2L2 | Oxidative stress-activated transcription factor for ARE-containing genes | Decreased activation of downstream antioxidant and iron metabolism proteins with FXN deficiency |
| PIP5K1β | PIP5K1B | Actin stabilization protein | Less PIP5K1 β protein production in FRDA due to cis-silencing, destabilizes actin filaments by loss of PI(4,5)P2 |
| Protoporphyrin IX | – | Final metal-free precursor of heme | Possible accumulation in absence of FXN Fe-delivery |
| ZO-1 | TJP1 | Scaffold protein of TJs which tethers peripheral junctional proteins to actin | Loss of junctional continuity at the cell periphery in models of mitochondrial stress and depressed oxidative phosphorylation |
A table of the key biomolecules highlighted in this review which contribute to the pathology of FRDA, as well as relevant proposed drug candidates. Gene symbol, function, and dysregulation in FRDA pathology are included where appropriate. See text for argumentation of FRDA and FECH interactions during heme biosynthesis. This table was designed with the intention of adequately reflecting the important focal points described in this review.