Document Type

Article

Publication Date

2-22-2022

Comments

This article is the author’s final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 119, Issue 8, February 2022, Article number e2115624119.

The published version is available at https://doi.org/10.1073/pnas.2115624119. Copyright © 2022 National Academy of Sciences. All rights reserved.

Abstract

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

35177476

Language

English

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