Deciphering the role of mitochondrial NDUFA11 in Parkinson's disease: An integrated study of bioinformatics and A53T mouse model

Parkinson's disease (PD) threatens public health seriously with its enigmatic pathogenesis and irreversible progression, and mitochondrial dysfunction plays a substantial role in the development of PD. Nevertheless, the specific mechanisms by which mitochondrial dysfunction aggravates PD remain unclear, thereby providing new insights into therapeutic options. We identified eight hub-mitochondrial-related differential expression genes (hub-MTDEGs) (NDUFA11, NDUFA8, NDUFA9, NDUFA1, NDUFB1, NDUFS7, COX7B, and COX14) and examined their mRNA levels in vitro and found that all except NDUFA1 were up-regulated in the MPP + -induced MN9D cell line. We selected NDUAF11 for further exploration. In the cellular experiments, the protein level of NDUAF11 was significantly elevated. Thereby, we transfected siRNA into the MPP + -induced MN9D cell line, primary astrocytes, and primary microglia and found that NDUFA11 knockdown aggravated the inflammatory response in the MN9D cell line and primary astrocytes. We found that both reactive oxidative species and mitochondrial membrane potential were further disturbed, and tyrosine hydroxylase deficiency was also observed. Finally, we validated hub-MTDEGs in five single-cell RNA sequencing datasets (GSE178265, GSE243639, GSE193688, PRJNA1145007, and GSE223138). Moreover, the protein level of NDUAF11 was significantly elevated in the PD mouse model and α-synuclein A53T mouse. Together, excluding known PD-relevant genes (NDUFA8, NDUFA9, and COX7B), we screened four novel hub-MTDEGs of PD (NDUFA11, NDUFB1, NDUFS7, and COX14), evidenced by significant transcriptional elevation, and experimentally targeted NDUFA11 in PD, demonstrating that its knockdown could worsen the mitochondrial dysfunction in vitro . Future experiments may be focused on the specific role of NDUAF11 in PD.