Significance Exploitation of mitochondrial functions promotes tumor traits, including metastasis, which is responsible for >90% of all cancer deaths. In this study, we investigated how mitochondrial fitness impacts tumor behavior. We found that acutely damaged, de-energized, and reactive oxygen species-producing mitochondria not only persist in cancer but are also key enablers of metastasis. These “ghost” mitochondria originate from the heterogeneous and often reduced expression of Mic60, an essential scaffold of organelle structure, in certain human cancers. The compensatory activation of gene expression programs as well as GCN2/Akt kinase signaling enables the survival of Mic60-low tumors but also provides a new therapeutic target in advanced and hard-to-treat malignancies.