MAPK-Driven Transformation Requires DRP1-Mediated Mitochondrial Division

Hyperactivation of the MAPK pathway via oncogenic mutation of upstream regulatory kinases, such as RAS and BRAF, occurs in a wide range of cancers and has been shown to promote mitochondrial dysfunction and metabolic reprogramming. Mitochondrial fragmentation has been detected in tumor cells and suggested to contribute to tumor growth; however, the mechanisms by which oncogenic RAS regulates mitochondrial dynamics and the role that this regulation plays in MAPK-driven tumorigenesis remain unclear. Serasinghe and colleagues found that expression of mutant RAS^G12V in untransformed cells led to upregulation of the mitochondrial fission regulator dynamin-related protein 1 (DRP1), increased mitochondrial fragmentation, and decreased mitochondrial function. Activation of DRP1 via ERK1/2–dependent phosphorylation at Ser616 (S616) was required for RAS-driven cellular transformation and correlated with BRAF^V600E status in human melanoma. In contrast, pharmacologic inhibition of oncogenic MAPK signaling in human cancer cells led to loss of DRP1 expression and activity, increased mitochondrial fusion, and enhanced mitochondrial function, thus sensitizing cancer cells to combined inhibition of MAPK and mitochondrial function. In agreement with these findings, Kashatus, Nascimento, and colleagues showed that loss of DRP1 inhibited RAS-induced mitochondrial fragmentation and impaired xenograft tumor growth in vivo. Activation of MAPK signaling via expression of constitutively active RAS, RAF, or MEK promoted ERK2-mediated DRP1 phosphorylation at S616, which was necessary for mitochondrial fragmentation and was reversed upon pharmacologic inhibition of MAPK signaling. Furthermore, DRP1 phosphorylation and mitochondrial fragmentation were observed in KRAS-mutant pancreatic cancer cell lines, and 7 of 12 patient-derived pancreatic tumor samples displayed a high level of colocalization between phosphorylated ERK and phosphorylated DRP1, as well as increased mitochondrial fragmentation. Together, these results emphasize the role of DRP1-mediated mitochondrial fission in MAPK-driven mitochondrial reprogramming and tumorigenesis and provide a rationale for exploiting mitochondrial dysfunction in tumors with high levels of phosphorylated DRP1.

Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, et al. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 2015;57:521–36.

Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 2015;57:537–51.