Using biosensors, reporter systems, and advanced microscopy, we will reveal how lysosomes orchestrate mitochondrial responses and iron-dependent cell death, uncovering hidden triggers of ferroptosis with therapeutic potential.
Project Details
Background:
Ferroptosis, an iron-dependent form of cell death, has emerged as a central process in cancer, neurodegeneration, and aging. While traditionally viewed as a cytosolic event, recent evidence points to lysosomes as hotspots for iron-driven oxidative damage. These organelles reduce Fe3⁺ to Fe2+, produce hydrogen peroxide, and create a local environment ideal for radical chemistry. The lysosomal channel TRPML1 controls Fe²⁺ and Ca²⁺ release, shaping mitochondrial ion supply and ferroptotic signaling. Yet, exactly how lysosomes and mitochondria communicate during ferroptosis remains a mystery. This project is part of TRPCat, where PhD students explore ion channels from the TRP family to uncover how ion signaling orchestrates cellular pathways. In this project, you will combine cutting-edge bioimaging and biosensor technologies to decipher the hidden dynamics of ferroptosis.
Hypothesis and Objectives:
We hypothesize that TRPML1-mediated release of Fe²⁺ and Ca²⁺ from lysosomes controls ferroptotic signaling through direct lysosome–mitochondria crosstalk. Interrupting this communication may reveal the hidden triggers of iron-dependent cell death and uncover organelle-specific mechanisms that remain largely unexplored. To address this, the project will: i) Develop novel biosensors and assays to track Fe²⁺, Ca²⁺, and oxidative events at the subcellular level in real time, offering unprecedented insight into ferroptosis dynamics. ii) Visualize and dissect lysosome–mitochondria communication, mapping TRPML1 activity and iron flow between organelles during ferroptotic signaling. iii) Reveal the mechanisms governing iron-dependent cell death, showing how lysosomal iron handling shapes mitochondrial responses and ferroptotic outcomes. iv) Translate these insights into experimental strategies to modulate ferroptosis, providing potential therapeutic avenues and innovative tools for the wider research community.
Methodology:
The project combines advanced molecular biology, live-cell imaging, and biosensor development1-3. You will employ high- and super-resolution fluorescence microscopy to capture signalling activities in real time and to visualize cellular organelles and their dynamics. Analysis of lysosome–mitochondria contacts and TRPML1 activity will be central, enabling a detailed mechanistic understanding of ferroptotic signaling from the subcellular to the molecular level. By integrating these approaches, you will develop novel experimental tools and uncover how lysosomes orchestrate life-or-death decisions in the cell.
References
1 Akyol, A; et al ACS Sens. 2025; 10(8):5854-5861 Doi: 10.1021/acssensors.5c01165
2 Pilic J et al Mol Cell. 2024; 84(14): 2732-2746.e5. Doi: 10.1016/j.molcel.2024.06.009
3 Erdoğan, YC; et.al. ACS Sens. 2024; 9(9):4680-4689 Doi: 10.1021/acssensors.4c01058
People Involved
Primary supervisor: Roland Malli
Collaborators: Benjamin Gottschalk