Mitochondrial stress disrupts insulin production in diabetes, but reversing the damage may restore β-cell function.
Mitochondria are essential for generating the energy that fuels cells and enables them to function.
However, mitochondrial defects are linked to the development of diseases such as type 2 diabetes. Patients with this disorder either cannot produce enough insulin or cannot effectively use the insulin their pancreas produces to maintain normal blood sugar levels.
Several studies have shown that the insulin-producing pancreatic β-cells of diabetic patients have abnormal mitochondria and fail to generate sufficient energy. Yet, these studies have not explained why the cells behave this way.
In a study published in Science, 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.”
The researchers also confirmed their findings in human pancreatic islet cells.
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.
Reversing mitochondrial damage could help cure diabetes
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.
Reference: “Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues” by 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 and Scott A. Soleimanpour, 6 February 2025, Science.
DOI: 10.1126/science.adf2034
Funding: Breakthrough T1D, NIH/National Institutes of Health, Department of Veterans’ Affairs, American Diabetes Association
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