Research Projects

Iron is vital for nearly all organisms due to its role in essential life processes such as synthesis of ATP, DNA and RBC. However, maintaining iron requirements in the human body (~ 1mM) is challenging because of the toxicity of free Fe²⁺ and the poor solubility of Fe³⁺ (~10⁻¹⁸ M). Abnormalities in systemic and cellular iron levels leads to anaemia and iron overload condition. To overcome this, organisms use ferritin, a nanocage protein that detoxifies iron, safely stores and releases it upon cellular requirements. However, the in vivo ferritin-iron dissolution/mobilization mechanisms are debatable and the associated regulatory mechanisms: how, when and at what rate, are not sufficiently understood. Ferritinophagy (a recently identified autophagic degradation pathway) is considered as a major mechanism for iron release. However, this process is energetically expensive, relatively slow, and may lead to iron bursts that might trigger oxidative stress. Is ferritinophagy the only universal mechanism across all organisms and conditions? Do quicker/economical iron release mechanisms exist? Given the reducing environment of the cytosol, reductive iron mobilization from intact ferritin is a plausible pathway. Yet, how this process is regulated—by redox partners, pore gating, or cage integrity—remains largely unknown. This question is especially relevant in iron overload disorders (e.g., thalassemia, hemochromatosis), where ferritin becomes iron-saturated and loses detoxification efficiency. Can ferritin be targeted using Fe³⁺ chelators or reduction-coupled chelation strategies to efficiently mobilize and clear excess stored iron? Bacterial pathogens also rely on ferritins and heme-containing bacterioferritins for iron storage and must mobilize iron during infection, under host-imposed iron limitation. Yet, how pathogens access iron from the host - whether via siderophores, proteolysis, or reductive pathways - is unclear and may vary across species and environmental conditions. More importantly, the mechanisms by which bacteria mobilize iron from their own ferritins/bacterioferritins during iron starvation are not fully elucidated. Findings from our lab, suggests that heme within bacterioferritin may mediate reductive iron release; possibly by acting as an electron mediator? In pathogens like Mycobacterium tuberculosis, increased heme content in bacterioferritin correlates with higher iron release. However, the physiological redox partners involved remain unidentified. Could disrupting these redox interactions inhibit iron release and microbial growth? This project seeks to address these unresolved questions, with the potential to advance our understanding of iron metabolism and identify new strategies for treating iron overload disorders (chelation therapy) and combating bacterial infections. Therefore, the following set of objectives has been framed. Objectives: 1. To identify and evaluate the effectiveness of Fe3+ chelators in facilitating non-reductive iron mobilization from intact ferritin protein cage. (for chelation therapy) 2. To find physiological/synthetic redox-couples (electron donor - mediator) for promoting dissolution and mobilization of iron from intact ferritins/bacterioferritins by reductive pathway. (for drug targets/reduction cum chelation therapy) 3. To study whether ferritin mineral can be used as iron source by microbes (pathogens), reveal their iron acquisition mechanisms and develop iron withholding strategies to control microbial growth (infection). (for anti-microbial activity) 4. To evaluate ferritinophagy as a ferritin-iron flux mechanism under pathophysiological conditions.