Oncogenic pathway utilizes mitochondrial fusion machinery to support growth

Mitochondria are cellular organelles with dynamic structure and function that respond to and synchronize with cellular signaling pathways. Reduced mitochondrial function results in cell cycle arrest,^1,2 and mutations in several genes encoding proteins with mitochondrial function have been described in specific types of cancer^3,4 Understanding the role of cellular signaling pathways in controlling mitochondrial function during development and disease is an exciting area of recent research.⁵

In a recent study,⁶ we investigated the effect of activating a number of cellular signaling pathways, particularly the ones that cause overgrowth and cancer, on the morphologies of mitochondria. We found that the conserved Yorkie/YAP signaling pathway, known for its role in the control of organ size,⁷ also has a role in regulating mitochondria in Drosophila as well as human cells that had not been described before. In Drosophila, activation of Yorkie achieved by expressing an activated version of the protein results in increased networking of mitochondria. Activation of Yorkie can be achieved either by directly expressing an activated version of the protein, or by causing loss of upstream members of the pathway that inhibit its activity. The mitochondrial function of Yorkie requires the TEAD domain protein Scalloped through direct transcriptional activation of genes encoding mitochondrial fusion proteins such as Opa1-like and Marf.⁸ In mammalian cells, activation of Yap results in lower reactive oxygen species (ROS) levels and genetic inhibition of mitochondrial fusion causes significant suppression in Yorkie-induced cell proliferation and tissue overgrowth in Drosophila. Activation of YAP2 in human cancer cell lines also causes increased mitochondrial fusion, suggesting functional conservation across species. In summary, mitochondrial fusion is an essential component of Yorkie/YAP pathway, with mitochondrial fusion proteins being direct targets of this signal, resulting in the regulation of cell proliferation and perhaps a similar role in oncogenesis.

Previously characterized targets of Yorkie/Yap pathway are cell cycle proteins such as cyclin E and the inhibitor of apoptosis DIAP-1 and the microRNA-encoding gene Bantam.⁹ This study identifies mitochondrial fusion genes and antioxidant scavenger protein-encoding genes as additional targets. Cyclin E has been shown to accumulate at a time when cells display a highly branched state of mitochondria in mammalian cells during G₁-S transition.¹⁰ We speculate that the simultaneous overexpression of mitochondrial components and proliferation genes further stabilizes the cells against apoptosis and causes growth. These results are significant from the point of view of uncontrolled growth and escape from apoptosis seen in tumor tissues harboring mutations in the YAP/Yki pathway.

Nagaraj R, Gururaja-Rao S, Jones KT, Slattery M, Negre N, Braas D, Christofk H, White KP, Mann R, Banerjee U. Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev. 2012;26:2027–37. doi: 10.1101/gad.183061.111.