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 invivo. 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.
Highlights
Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood
Mic[60] is an essential constituent of a MICOS complex (16) that maintains cristae architecture (17), organizes respiratory complexes (18), and ensures outer membrane biogenesis (19). Whether this pathway is important in cancer has not been determined, but there is evidence that Mic[60] participates in mitochondrial fitness, including PINK1/Parkin-directed mitophagy (20) and mitochondrial dynamics (21)
We found that acutely damaged, de-energized, and reactive oxygen species-producing mitochondria persist in cancer but are key enablers of metastasis
Summary
Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic[60] depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. 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. Mic[60] is an essential constituent of a MICOS complex (16) that maintains cristae architecture (17), organizes respiratory complexes (18), and ensures outer membrane biogenesis (19) Whether this pathway is important in cancer has not been determined, but there is evidence that Mic[60] participates in mitochondrial fitness, including PINK1/Parkin-directed mitophagy (20) and mitochondrial dynamics (21). We investigated how mitochondrial fitness may impact cancer traits and potentially expose therapeutic vulnerabilities in advanced disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
