Autophagy: NMR and MS reveal tumour regrowth mechanism

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  • Published: Sep 1, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Autophagy: NMR and MS reveal tumour regrowth mechanism

Regrowth

The combined forces of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry have been used in research that shows how cell metabolism affects the ability of cells to undergo a survival program called autophagy during cancer chemotherapy allowing a tumour to regrow.

The combined forces of Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry have been used in research that shows how cell metabolism affects the ability of cells to undergo a survival program called autophagy during cancer chemotherapy allowing a tumour to regrow.

It is known that cells can adapt to deprivation in terms of nutrient and energy supply by inducing autophagy. This process, self-eating, is regulated by two types of proteins: the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) enzymes. Now, researchers from the University of Cincinnati (UC) College of Medicine have demonstrated that mitochondrial complex I is critical in autophagy. Specifically, it controls initiation as well as the size and duration of the response. Autophagy rises with increased mitochondrial metabolism but the anti-diabetic drugs phenformin and metformin or genetic defects in complex I can suppress it, the team reports.

Metabolic cues

Moreover, they have found that mTOR inhibitors also increase select phospholipids and mitochondrial-associated membranes (MAMs) significantly in a way that depends on complex I. This represents a shift away from glycolysis and towards mitochondrial metabolism, which enhances autophagy through increased phospholipid metabolism.

"We attribute the complex I autophagy defect to the inability to increase MAMs, limiting phosphatidylserine decarboxylase (PISD) activity and mitochondrial phosphatidylethanolamine (mtPE), which support autophagy," the team explains. Thus they demonstrate dynamic and metabolic regulation of autophagy, which has important implications for the outcome of antitumour therapies.

Dynamic autophagy

"Our data reveal the dynamic and metabolic regulation of autophagy and suggest new therapeutic strategies for cancer, neurodegenerative and mitochondrial diseases," Mercer adds. "We need to further explore the reasons this occurs and the implications for how the metabolic regulation of autophagy can be used in the clinic."

It is possible that the new insights could be exploited to trigger cell metabolism itself to "pull the plug” on tumour cells that have survived chemotherapy. This might one day lead to better treatments that preclude the return of a tumour and lead to complete remission.

This research was supported by the NMR Metabolomics Core (Lindsey Romick-Rosendale, director) at Cincinnati Children’s Hospital Medical Center and the Clinical Mass Spectrometry Core (Kenneth Setchell, director) there. It was funded by the National Cancer Institute (R21CA191814) and a UC Hematology Oncology Translational Science and Pilot Grant Award.

Related Links

Cell Rep 2018, online: "Mitochondrial Complex I Activity Is Required for Maximal Autophagy"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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