Processes enlisted to mitigate cytotoxicity in metabolically stressed cells evoke invasive behavior in other cells. Three sequential events contribute to mechanisms through which metabolic stress may be communicated between cells: (1) Mitochondrial damage/depolarization increases levels of PINK1 to promote physical interaction of late endosomes with mitochondria. This leads to transfer of the mitochondrial chromosome into the lumen of intraluminal vesicles of late endosomes; (2) a combination of glutaminolysis and up-regulation of xCT (SLC7A11) leads to increased secretion of glutamate to drive Rab27-dependent exocytosis of EVs loaded with mtDNA; and (3) mtDNA transported within these EVs activates a TLR9-dependent mechanism to promote pro-invasive endosomal trafficking of MT1-MMP in other cells.