Researchers at the University of Michigan have discovered that dysfunctional mitochondria trigger a stress response in cells, leading to impaired maturation and function, particularly in insulin-producing pancreatic β-cells. This stress response is implicated in the development of type 2 diabetes. The study found that damaging mitochondrial components activated the same stress response across different cell types affected by diabetes, including liver and fat-storing cells.
Mitochondrial defects, however, are associated with the development of diseases such as type 2 diabetes. Patients who suffer from this disorder are unable to produce enough insulin or use the insulin produced by their pancreas to keep their blood sugar at normal levels.
Several studies have shown that insulin-producing pancreatic β-cells of patients with diabetes have abnormal mitochondria and are unable to generate energy. Yet, these studies were unable to explain why the cells behaved this way., researchers at the University of Michigan used mice to show that dysfunctional mitochondria trigger a response that affects the maturation and function of β-cells. "We wanted to determine which pathways are important for maintaining proper mitochondrial function," said Emily M. Walker, Ph.D, a research assistant professor of internal medicine and first author of the study. To do so, the team damaged three components that are essential for mitochondrial function: their DNA, a pathway used to get rid of damaged mitochondria, and one that maintains a healthy pool of mitochondria in the cell. "In all three cases, the exact same stress response was turned on, which caused β-cells to become immature, stop making enough insulin, and essentially stop being β-cells," Walker said. "Our results demonstrate that the mitochondria can send signals to the nucleus and change the fate of the cell."Mitochondrial dysfunction affects several types of cells Their results prompted the team to expand their search into other cells that are affected during diabetes. "Diabetes is a multi-system disease -- you gain weight, your liver produces too much sugar and your muscles are affected. That's why we wanted to look at other tissues as well," said Scott A. Soleimanpour, M.D., director of the Michigan Diabetes Research Center and senior author of the study. The team repeated their mouse experiments in liver cells and fat-storing cells and saw that the same stress response was turned on. Both cell types were unable to mature and function properly. "Although we haven't tested all possible cell types, we believe that our results could be applicable to all the different tissues that are affected by diabetes," Soleimanpour said.Regardless of the cell type, the researchers found that damage to the mitochondria did not cause cell death. This observation brought up the possibility that if they could reverse the damage, the cells would function normally. To do so, they used a drug called ISRIB that blocked the stress response. They found that after four weeks, the β-cells regained their ability to control glucose levels in mice. "Losing your β-cells is the most direct path to getting type 2 diabetes. Through our study we now have an explanation for what might be happening and how we can intervene and fix the root cause," Soleimanpour said. The team is working on further dissecting the cellular pathways that are disrupted and hope that they will be able to replicate their results in cell samples from diabetic patients.Emily M. Walker, Gemma L. Pearson, Nathan Lawlor, Ava M. Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C. Reck, Jin Li, Elena Levi-D’Ancona, Mabelle B. Pasmooij, Dre L. Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S. Parekh, Irina X. Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A. Ware, Leena Haataja, Nathan Qi, Stephen C. J. Parker, Peter Arvan, Lei Yin, Brett A. Kaufman, Leslie S. Satin, Lori Sussel, Michael L. Stitzel, Scott A. Soleimanpour.The research team administered AP39 to some worms from birth, and to others after reaching adulthood. They found that this compound improved the integrity of mitochondria -- the 'power house' of ... Diseases that affect mitochondria -- specialized compartments within cells that contain their own DNA and convert the food we eat into energy needed to sustain life -- typically interfere with ... Mitochondria are the power plants of our cells and play an important role in providing energy for normal function of the tissues in our body. Thanks to a metabolic adjustment, cells can remain ... To function properly, the heart needs energy from cells' powerhouses, the mitochondria. In turn, mitochondria boost their energy output when calcium levels rise around them, a signal that more energy ...Working Dogs Take a Day to Adjust to Daylight Savings Time, but Pets Are More Flexible
MITOCHONDRIA DIABETES CELLULAR STRESS INSULIN PRODUCTION TISSUE FUNCTION
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