Mitochondria are highly dynamic and undergo constant fusion and fission that are 
essential for maintaining physiological functions of cells. Although dysfunction 
of mitochondria has been implicated in tumorigenesis, little is known about the 
roles of mitochondrial dynamics in metastasis, the major cause of cancer death. 
In the present study, we found a marked upregulation of mitochondrial fission 
protein dynamin-related protein 1 (Drp1) expression in human invasive breast 
carcinoma and metastases to lymph nodes. Compared with non-metastatic breast 
cancer cells, mitochondria also were more fragmented in metastatic breast cancer 
cells that express higher levels of total and active Drp1 and less mitochondrial 
fusion protein 1 (Mfn1). Silencing Drp1 or overexpression of Mfn1 resulted in 
mitochondria elongation or clusters, respectively, and significantly suppressed 
metastatic abilities of breast cancer cells. In contrast, silencing Mfn proteins 
led to mitochondrial fragmentation and enhanced metastatic abilities of breast 
cancer cells. Interestingly, these manipulations of mitochondrial dynamics 
altered the subcellular distribution of mitochondria in breast cancer cells. For 
example, silencing Drp1 or overexpression of Mfn1 inhibited lamellipodia 
formation, a key step for cancer metastasis, and suppressed 
chemoattractant-induced recruitment of mitochondria to lamellipodial regions. 
Conversely, silencing Mfn proteins resulted in more cell spreading and 
lamellipodia formation, causing accumulation of more mitochondria in 
lamellipodia regions. More importantly, treatment with a mitochondrial 
uncoupling agent or adenosine triphosphate synthesis inhibitor reduced 
lamellipodia formation and decreased breast cancer cell migration and invasion, 
suggesting a functional importance of mitochondria in breast cancer metastasis. 
Together, our findings show a new role and mechanism for regulation of cancer 
cell migration and invasion by mitochondrial dynamics. Thus targeting 
dysregulated Drp1-dependent mitochondrial fission may provide a novel strategy 
for suppressing breast cancer metastasis.