Abstract

Pmpcb (peptidase, mitochondrial processing beta subunit) gene encodes the catalytic subunit of mitochondrial processing peptidase, and its mutation is associated with human multiple mitochondrial dysfunction syndrome type 6 (MMDS6), presenting with severe neurodegenerative lesions clinically. Nonetheless, the potential molecular mechanisms underlying pmpcb deficiency induced abnormal development of the central nervous system (CNS) and the related diseases have not been fully elucidated. In this study, we found that zebrafish larvae with a functional deficiency of pmpcb ( pmpcb −/− ) exhibited reduced neural cells, uncompacted myelin, and dysfunctional locomotor behaviors. Mechanistically, the decrease in mitochondrial membrane potential and insufficient ATP synthesis in pmpcb −/− zebrafish contributes to elevated reactive oxygen species (ROS) stress and endoplasmic reticulum (ER) stress and the consequent neural cell apoptosis. These partially impaired WNT/β-Catenin signaling activities and the subsequent neural cell formation, ultimately associating with the CNS and locomotor behavior defects in zebrafish. Meanwhile, WNT agonist 6-Bromoindirubin-3’-oxime (BIO), ATP precursor creatine (CRE), ER stress scavenger 4-phenylbutyric acid (PBA), and glial cell specific gene gfap ( glial fibrillary acidic protein ) promoter driven stable expression of pmpcb (Tg( gfap : pmpcb )), each effectively mitigated the CNS defects in the pmpcb −/− mutants. Additionally, larvae of the Tg( gfap : pmpcb ) line were more resistant to heavy metal stress and bacterial infection. This study demonstrates for the first time the significance of Pmpcb’s role in CNS development, stress resistance and locomotor behavior. Our findings provide new insights into the mechanisms and potential diagnostic strategies for the related diseases. Graphical Working model of pmpcb in regulating the development of the central nervous system. The alternative text for this image may have been g