Researchers at the Yale School of Medicine have discovered a connection between mitochondrial size and regulation of blood glucose levels, suggesting that mitochondria-shaping mechanisms can be altered to develop potential diabetes treatments.
Led by medical school professor Sabrina Diano, the research team investigated the intracellular mechanisms that enable hypothalamic neurons to sense and respond to circulating peripheral signals, including those of nutrients such as glucose. The study, which was published in Cell Metabolism on Feb. 9, revealed the impact of mitochondria-shaping processes on the activation of the neurons that control blood sugar levels.
“Our research has, for the first time, fully demonstrated the role of the dynamin-related protein, DRP1 — which controls mitochondrial fission, or the splitting of mitochondria — in the regulation of glucose and energy homeostasis,” said Anna Santoro, a postdoctoral associate and the first author on the study.
According to a 2011 Nature Medicine paper by Diano, reactive oxygen species, ROS, are important regulators of hypothalamic proopiomelanocortin, POMC, neurons, which control energy and glucose metabolism.
Because a large amount of ROS is produced by mitochondria during the oxidation of substances like glucose and fatty acids, the group’s research focused on how changes in mitochondria — in both size and function — in POMC neurons affect energy and glucose homeostasis, Diano explained.
To understand how changes in mitochondrial size impact activation of these neurons and thus glucose metabolism, the researchers targeted DRP1, because this protein induces mitochondria to undergo fission. They designed two mouse models: one in which DRP1 was deleted during development and one in which the protein was deleted in adult POMC neurons, Diano said.
According to Santoro, the first mouse model showed a reduction in the number of POMC neurons, and the mice later developed obesity and Type 2 diabetes. This highlighted the importance of DRP1 in the regulation of POMC neurons’ development and its relevance in the control of whole-body energy metabolism.
However, in the second model, in which DRP1 was deleted temporally in mature POMC cells, the mice did not develop obesity or diabetes and instead showed an increased response to changes in glucose levels, Diano said. Their glucose metabolisms were significantly improved, compared to that of control mice, she added.
“With the second mouse model, we have demonstrated that DRP1 negatively affects POMC neurons’ ability to keep blood sugar levels within a safe range,” Santoro said.
Diano explained that the researchers discovered that the mitochondria of activated hypothalamic glucose-sensing POMC neurons are bigger than those observed in silent POMC neurons. This finding was further supported when they found that the expression of DRP1 — causing mitochondria to divide into two smaller organelles — is lowered in activated POMC neurons.
According to Santoro, this suggests that DRP1 lowers the ability of POMC neurons to regulate blood glucose levels, as DRP1-mediated mitochondrial fission may function as a mechanism to silence the glucose-sensing neurons.
“We indeed found that when DRP1 was deleted in mature POMC neurons, these neurons were more active and more responsive to changes in glucose levels,” Diano said. “This, in turn, induced an improved whole-body glucose metabolism.”
Furthermore, the investigators analyzed DRP1 expression and mitochondrial size in POMC neurons of mice that had been fed and had fasted. Comparing the two groups of mice, they found that fed mice had decreased DRP1 activation and increased mitochondrial size. The result implies that mitochondrial fusion — the opposite of fission — may be required to activate POMC neurons, according to the paper.
The discoveries of this study provide insight into developing new diabetes treatments, Santoro said. DRP1 could become a novel therapeutic target for treating Type 2 diabetes and enhancing counterregulatory responses to hypoglycemia. This condition, also known as low blood sugar, is one of the most severe complications from Type 1 diabetes treatments like insulin injections, Santoro added.
According to Diano, the researchers will further investigate how these size changes in the mitochondria relate to the function of the organelle in POMC neurons.
They also hope to test the effects of DRP1 inhibitors in both Type 1 and Type 2 diabetes mouse models to demonstrate their ability to improve the control of glycemia, Santoro said.
About 29 million Americans, or 9.3 percent of the population, have some form of diabetes, according to the American Diabetes Association.