Open AccessGhost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability
Author(s) -
Jagadish C. Ghosh,
Michela Perego,
Ekta Agarwal,
Irene Bertolini,
Yuan Wang,
Aaron R. Goldman,
HsinYao Tang,
Andrew V. Kossenkov,
Catherine Libby,
Lucia R. Languino,
Edward F. Plow,
Annamaria Morotti,
Luisa Ottobrini,
Marco Locatelli,
David W. Speicher,
M. Cecilia Caino,
Joel Cassel,
Joseph M. Salvino,
Marie E. Robert,
Valentina Vaira,
Dario C. Altieri
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2115624119
Subject(s) - mitochondrion , biology , protein kinase b , microbiology and biotechnology , cancer research , metastasis , signal transduction , pi3k/akt/mtor pathway , cancer , genetics
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.