Hinokitiol restores hemoglobinization and mitigates neurodegeneration in animals by re-establishing iron homeostasis

Ekaputri, Stella

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https://hdl.handle.net/2142/129647 Copy

Description

Title

Hinokitiol restores hemoglobinization and mitigates neurodegeneration in animals by re-establishing iron homeostasis

Author(s)

Ekaputri, Stella

Issue Date

2023-09-22

Director of Research (if dissertation) or Advisor (if thesis)

Burke, Martin

Doctoral Committee Chair(s)

Burke, Martin

Committee Member(s)

• Schroeder, Nathan
• Nair, Satish
• Zhang, Kai

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Hinokitiol
• iron misdistribution
• iron redistribution
• anemia
• ferroportin

Abstract

Iron misdistribution disorder is characterized by iron accumulation and iron deficiency in various sites due to ferroportin (FPN1) dysfunction. Genetic FPN1 deficiency causes Ferroportin disease (FD), which is characterized by iron deposition in liver macrophages and anemia. Aside from loss-of-function genetic mutations, FPN1 deficiency can be induced by inflammation. Therefore, iron misdistribution also underlies various diseases associated with chronic inflammation, such as rheumatoid arthritis, type 2 diabetes, cardiovascular disease, cancer, chronic kidney disease (CKD), or aging. Although FD has been extensively characterized, causative link between iron misdistribution and diseases associated with inflammation, specifically aging, has not been established. As the world’s older population continues to grow at unprecedented rate, a variety of aging-related diseases have gradually become the most important causes of disability and death in elderly individuals. One of the most common age-related diseases is Parkinson’s Disease (PD). Increased iron accumulation in substantia nigra has been reported in PD patients, suggesting that there is association between iron dyshomeostasis and neurodegeneration. Iron levels in substantia nigra have also been reported to increase linearly with age and this has been associated with progressive motor dysfunction in elderly. Despite its prevalence, there is no current treatment for iron misdistribution. For instance, FD patients are still treated with venesection/phlebotomy, which fails to address the underlying issue. Due to the unique nature of iron misdistribution disorder, for a molecule to successfully treat this disorder, it must be able to perform iron redistribution until iron homeostasis is reached. Previously, we have shown that hinokitiol can perform a protein-like function to replace the missing iron transporters. Its unique ability to perform site- and direction-specific iron mobilization to restore iron homeostasis resulted in physiological restoration in various animal models of anemia. We hypothesize that hinokitiol can also perform iron redistribution. Using flatiron mice, a mouse model of FD, as well as various biochemical and cell-based assays, we show that hinokitiol redistributes iron from liver macrophages to serum transferrin and promotes hemoglobinization in transferrin-dependent manner. We also show that hinokitiol interfaces with endogenous proteins and re-establishes iron homeostasis. Our current understanding of how hinokitiol restores physiology in FPN1-deficient flatiron mice allowed us to use it as a chemical probe to study the causative link between iron dyshomeostasis and neurodegeneration. Here we report that hinokitiol and its functionally similar derivative, FeM-1269, could mitigate neurodegeneration in FPN1-deficient C. elegans by re-establishing iron homeostasis. We also show that simple iron removal mediated by an FDA-approved iron chelator deferiprone (DFP) can lead to cellular iron deficiency, leading to perturbation of neuronal homeostasis. These results not only establish that iron homeostasis is essential for proper neural functioning, but they also suggest a unique alternative to treat neurodegeneration associated with iron dyshomeostasis.

Graduation Semester

2023-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/129647

Copyright and License Information

Copyright 2023 Stella Ekaputri

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