Transglutaminase 2 (TG2) is a widespread enzyme in the transglutaminase family, which consists of nine multifunctional proteins that evolved from the papain family. TG2 is ubiquitously expressed across various tissues and cell types. Its primary role is catalyzing the formation of a durable isopeptide bond through the Ca2+-dependent covalent linkage between the γ-carboxamide group of peptide-bound glutamine and the ε-amino group of lysine in proteins. This enzymatic process results in a proteolytically-resistant bond. Significantly, TG2 activity is observed to increase in several neurodegenerative diseases, including Parkinson's disease (PD), which has led to focused research on its role and mechanisms in these conditions. Our study has uncovered that inducing mitochondrial dysfunction by inhibiting mitochondrial complex 1, replicating the molecular damage observed in PD's nervous system, western blot and activity assays led to significant elevation in both protein expression and crosslinking activity of TG2, respectively. Consequently, using high-throughput analysis, such as Data-Independent Acquisition analysis (DIA) proteomics on captured biotin-labeled proteins identified TG2-mediated proteins associated with to PD, such as chromatin organization, regulation of plasma membrane, etc. In summary, the results deepen our understanding of the intricate interplay between TG2 substrates and the correlated molecular pathways that underline PD. Therefore, nominating TG2 as a candidate molecular biomarker of Parkinson's disease.