Abstract
Previous study showed that lead (Pb) could induce ATM-dependent mitophagy. However, whether Pb has any impact on mitochondrial fusion and fission, the upstream events of mitophagy, and how ATM connects to these processes remain unclear. In this study, we found that Pb can disrupt mitochondrial network morphology as indicated by increased percentage of shortened mitochondria and by decreased mitochondrial footprints. Correspondingly, the expression of fission protein Drp1 and its association with mitochondrial marker Hsp60 were significantly increased, while those of fusion proteins Mfn2 and Opa1 and their co-localization with Hsp60 were drastically attenuated. Notably, the expression of p-Drp1 (Ser616) and its translocation to mitochondria were dramatically elevated. Moreover, a small amount of ATM could be detected in the cytoplasm around mitochondria in response to Pb, and the co-localization of p-ATM (Ser1981) with Drp1 and p-Drp1 (Ser616) was obviously increased while its co-localization with Mfn2 and Opa1 was dramatically decreased. Furthermore, siRNA silencing of ATM evidently promoted greater fission in response to Pb stress, indicating that ATM is involved in mitochondrial fragmentation. Our results suggest that cytoplasmic ATM is an important regulator of Pb-induced mitochondrial fission.