Objective To investigate the rescue effect of Drp1 gene over-expression on drosophila models of Parkinson's disease (PD) and their specific mechanism using iTRAQ-based proteomic technology. Methods The drosophilae from 3 groups, control group, PD group (PINK1 mutant), and rescue group (PINK1 mutant+Drp1 over-expression) were cultured at routine ways. The wing shape and movement ability of drosophilae were observed, and the percentages of drosophilae having abnormal wings and normal flight were calculated. The proteomic changes were determined by iTRAQ technology; the functions and signaling pathways of the differential expressed proteins were analyzed by GO and KEGG pathway enrichment analyses. Results Percentage of drosophilae having abnormal wings in the rescue group (2.60％±0.47％) was significantly decreased as compared with that in the PD group (82.40％±12.47％, P<0.05), and the percentage of drosophilae having normal flight in the rescue group (89.70％±7.76％) was significantly increased as compared with that in the PD group (3.30％±1.69％, P<0.05). A total of 3630 proteins were identified using iTRAQ; 282 differential expressed proteins between the PD group and control group were detected, which mainly were iron ion related proteins; 170 differential expressed proteins between the PD group and rescue group were detected, which mainly were zinc ion related proteins. GO and KEGG pathway enrichment analyses on these co-differential expressed proteins revealed that 21％ proteins had metal ion binding activity, especially zinc ion. Conclusion Abnormal iron homeostasis, especially zinc homeostasis, participates in PD pathophysiological processes and over-expressing Drp1 rescued PD processes.