Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron’s contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health.

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/β-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator-activated receptor α (PPARα) agonist, fenofibrate, prevents iron-induced oxidative stress and β-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD-dependent deacetylase, that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury (IRI) by normalizing the Wnt/β-catenin pathway. In the present study, we explored if fenofibrate prevents iron-induced liver injury by regulating the Sirt3 and β-catenin signaling. In vitro and in vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active β-catenin, and its downstream target gene in the mouse liver. Pharmacological activation of Sirt3, both in vitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active β-catenin expression and prevented the iron-induced upregulation of α smooth muscle actin () and expression. Intrinsically, PPARα knockout mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron-induced downregulation of liver Sirt3 and active β-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3, and β-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron-induced liver injury likely has significant therapeutic impact on iron-associated chronic liver diseases. Hepatic intracellular iron accumulation has been implicated in the pathophysiology of chronic liver diseases. In this study, we identified a novel mechanism involved in the progression of fibrosis. Excess iron accumulation in liver caused downregulation of PPARα-Sirt3-Wnt signaling leading to fibrosis. This work has significant translational potential as PPARα agonist fenofibrate could be an attractive therapeutic drug for the treatment of liver disorders associated with iron overload.

Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin-angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin-angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.

Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.

Heterotrimeric G-protein transducin, Gt, is a key signal transducer and amplifier in retinal rod and cone photoreceptor cells. Despite similar subunit composition, close amino acid identity, and identical posttranslational farnesylation of their Gγ subunits, rods and cones rely on unique Gγ1 (Gngt1) and Gγc (Gngt2) isoforms, respectively. The only other farnesylated G-protein γ-subunit, Gγ11 (Gng11), is expressed in multiple tissues but not retina. To determine whether Gγ1 regulates uniquely rod phototransduction, we generated transgenic rods expressing Gγ1, Gγc, or Gγ11 in Gγ1-deficient mice and analyzed their properties. Immunohistochemistry and Western blotting demonstrated the robust expression of each transgenic Gγ in rod cells and restoration of Gαt1 expression, which is greatly reduced in Gγ1-deficient rods. Electroretinography showed restoration of visual function in all three transgenic Gγ1-deficient lines. Recordings from individual transgenic rods showed that photosensitivity impaired in Gγ1-deficient rods was also fully restored. In all dark-adapted transgenic lines, Gαt1 was targeted to the outer segments, reversing its diffuse localization found in Gγ1-deficient rods. Bright illumination triggered Gαt1 translocation from the rod outer to inner segments in all three transgenic strains. However, Gαt1 translocation in Gγ11 transgenic mice occurred at significantly dimmer background light. Consistent with this, transretinal ERG recordings revealed gradual response recovery in moderate background illumination in Gγ11 transgenic mice but not in Gγ1 controls. Thus, while farnesylated Gγ subunits are functionally active and largely interchangeable in supporting rod phototransduction, replacement of retina-specific Gγ isoforms by the ubiquitous Gγ11 affects the ability of rods to adapt to background light.