Researchers have discovered a mechanism through which mitochondria, the energy factory of our body's cells, play a role in preventing cells from dying when the cells are deprived of nutrients - a finding that points to a potential target for next-generation cancer drugs.
The research, published in the journal Molecular Cell.
Cells in our body grow in size, mass and numbers through a process governed by a master regulator known as mTOR (Mechanistic Target of Rapamycin). Researchers discovered years ago that mTOR also controls protein expression in all human cells. In particular, mTOR targets the selective synthesis of proteins destined for the mitochondria, that generate the energy needed for cells to grow and divide.
The team have now shown that mTOR also controls the expression of proteins that alter the structure and function of mitochondria -- thereby protecting cells from dying.
Authors demonstrate that the mTOR stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1).
Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic.
Thus the new study reveals that mitochondria help keep these cells alive by fusing together and blocking a central point in a cell death pathway, called apoptosis.
Their work has implications for cancer therapy, since new drugs that act on mTOR are currently in clinical trials for cancer. While the treatments are effective in arresting the expansion and growth of cancer cells, the cells continue to survive, despite a shortage of nutrients. This advance offers clues to develop combination therapies that could promote cancer-cell death by reversing the protection offered by mitochondria, the researchers say.
Mitochondria drive cell survival in times of need
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