The mitochondria inside oxygen-deprived cells don’t wheeze and gasp. They reduce their numbers and alter their metabolism, dispensing with respiration and relying, instead, on glycolysis. The adaptation, which helps sustain cancer cells deep within tumors, involves the activation of a lipid signaling pathway, report scientists based at the Max Planck Institute for Biology of Aging. According to these scientists, disrupting the pathway could reduce tumor growth. In fact, the scientists demonstrated this possibility by switching off the signaling pathway in cells originating from patients with pancreatic tumors.
“It has been known for some time that cells reduce the number of mitochondria when they lack oxygen and switch to glycolysis,” noted Thomas Langer, PhD, a director at Max Planck. “We have now discovered that the remaining mitochondria are additionally reprogrammed to meet the new requirements.”
The reprogramming may be necessary in old age, for example, as the cells in the body are often less supplied with oxygen and nutrients. However, the reprogramming can also benefit cancer cells that face the challenge of poor blood supply, and hence being starved of oxygen and nutrients.
By uncovering details of the reprogramming mechanism, Langer’s Max Planck team hopes to inform new anticancer strategies. The scientists are particularly interested in identifying good targets for therapies against pancreatic cancer, for which no drug is currently available.
Details of the team’s work appeared November 6 in the journal Nature, in an article titled, “Lipid signaling drives proteolytic rewiring of mitochondria by YME1L.” The article describes how YME1L, a protease in the membrane of mitochondria, is activated during the conversion to glycolysis and then breaks down various proteins in the organelles.
“YME1L rewires the proteome of preexisting mitochondria in response to hypoxia or nutrient starvation,” the article’s authors wrote. “Inhibition of mTORC1 induces a lipid signaling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis.”
YME1L degrades mitochondrial protein translocases, lipid transfer proteins, and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. This process eventually stops on its own, as the protease begins to degrade itself at high activity. “This signaling pathway not only has a built-in timer, but also enables a very rapid response to oxygen deficiency,” noted Langer.
“YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts,” the authors continued. “Similar changes to the mitochondrial proteome occur in the tumor tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumors.”
Pancreatic tumors grow under oxygen deficiency and are highly aggressive. After experimenting with cancer cells originating from patients with pancreatic tumors, the scientists observed that tumor growth could be reduced by switching off the signaling pathway in the mitochondria. This was seen in cancer cells in the Petri dish as well as in pancreatic tumors in mice.
“I believe that this protease can be a very interesting therapeutic target because we have seen that the signaling pathway is also active in human patients with pancreatic cancer,” Langer emphasized. However, he added that substances that could affect the protease have yet to be identified.