期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：8
DOI：10.1073/pnas.2115624119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, “ghost” mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.
