Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

Altered mitochondrial trafficking as a novel mechanism of cancer metastasis

“…Surprisingly, MIRO2 was dispensable for SNPH's functions. In follow‐up studies, we uncovered a novel isoform of SNPH that localizes to the mitochondrial matrix and maximizes the activity of the OxPhos complex II . Thus, SNPH knockdown increased mitochondrial superoxide production and oxidative stress‐dependent tumor cell motility.…”

“…Thus, a cancer cell can reprogram mitochondrial localization to respond to extracellular and intracellular cues and switch between highly proliferative (when mitochondria are perinuclear) and a highly invasive (when mitochondria are at the leading edge) phenotype. Indeed, it has been shown that key regulators of mitochondrial trafficking via microtubules control the balance between proliferation and motility (see below).…”

“…Thus, SNPH knockdown increased mitochondrial superoxide production and oxidative stress‐dependent tumor cell motility. Importantly, endogenous metastatic tumors in mice displayed lower SNPH levels and enhanced markers of oxidative stress and epithelial to meshenchymal transition (EMT) . Furthermore, this novel intramitochondrial SNPH isoform was able to block metastatic dissemination in a syngeneic melanoma mice model .…”

“…Importantly, endogenous metastatic tumors in mice displayed lower SNPH levels and enhanced markers of oxidative stress and epithelial to meshenchymal transition (EMT) . Furthermore, this novel intramitochondrial SNPH isoform was able to block metastatic dissemination in a syngeneic melanoma mice model . Given this role of SNPH in modulating cell metabolism and proliferation versus motility of cancer cells, it was not surprising that hypoxic or oxidative stress quickly downregulated SNPH expression .…”

“…Furthermore, this novel intramitochondrial SNPH isoform was able to block metastatic dissemination in a syngeneic melanoma mice model . Given this role of SNPH in modulating cell metabolism and proliferation versus motility of cancer cells, it was not surprising that hypoxic or oxidative stress quickly downregulated SNPH expression . SNPH was also downregulated in tumors with mutations or deletions of von Hippel‐Lindau (VHL), the negative regulator of the hypoxia inducible transcription factors.…”