Targeting the mitochondrial Ca2+ set point to intercept ferroptosis in Parkinson’s disease

• Applicant: Dr. Li Zhang
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 581819249

Parkinson’s disease (PD) affects more than 10 million people worldwide and remains a major cause of disability. Progressive loss of substantia nigra dopaminergic neurons underlies motor symptoms, yet the initiating death pathway and its earliest controllable trigger are unresolved. Converging evidence implicates ferroptosis—an iron-dependent, lipid-peroxidation–driven process—as a contributor, but two questions remain central: (i) is ferroptosis truly a shared mechanism across PD genotypes, and (ii) what upstream checkpoint commits neurons to ferroptotic vulnerability? Our cross-model work in genetic Drosophila PD lines shows that ferroptosis inhibitors consistently rescue behavior/survival across genotypes, indicating that ferroptotic stress is measurable and targetable in vivo. However, chronic late-stage ferroptosis inhibition may be systemically burdensome. A safer strategy is to stabilize an upstream, adjustable set point before commitment. Mitochondrial Ca²⁺ (mtCa²⁺) stands out as such a candidate: in Pink1 mutants we captured hallmarks of bona fide ferroptosis, and partially lowering mtCa²⁺ (Mcu+/–) reduced lipid peroxidation and rescued behavior. Importantly, Mcu+/– also improved motor performance in park mutants where lipid peroxidation is elevated, and pharmacological ferroptosis inhibitors rescued phenotypes across park, LRRK2, and GBA models. Together, these results support an mtCa²⁺–ferroptosis axis as a shared pathway in PD and motivate direct tests of mtCa²⁺ stabilization versus ferroptosis inhibition. Accordingly, the project will establish the mtCa²⁺–ferroptosis axis across Drosophila PD models with time-resolved readouts (mtCa²⁺, iron speciation, lipid peroxidation) to define when mtCa²⁺ elevation first predicts ferroptotic chemistry and functional decline; dissect how mtCa²⁺ elevation propagates into iron-redox shifts and polyunsaturated-lipid peroxidation in both Drosophila and mouse models, including potential feedback loops that reinforce mtCa²⁺ loading and thereby distinguish initiating signals from self-amplifying stress; and translate to the human context by benchmarking mtCa²⁺ stabilization versus ferroptosis inhibition in patient-derived PINK1 p.Q456X dopaminergic neurons to determine whether early mtCa²⁺ control preserves viability and redox balance more effectively than late ferroptosis blockade. By resolving when and how mtCa²⁺ governs entry into ferroptosis—and by defining an actionable early-stabilization window—this project reframes intervention away from chronic, systemic ferroptosis inhibition toward precision control of an upstream mitochondrial set point. If validated, mtCa²⁺ stabilization offers a disease-relevant, drug-adjustable checkpoint with the potential to generalize across PD genotypes and improve translational feasibility.

• DFG Programme: Research Grants