Mitochondria are essential for generating energy that fuels cells and helps them function.

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.

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.  

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."

-Scott A. Soleimanpour, M.D.

“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.

Additional authors: 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 and Michael L. Stitzel.

Funding/disclosures: Soleimanpour was supported by Breakthrough T1D (CDA-2016-189, COE-2019-861, SRA-2023-1392, SRA-2024-1586), the NIH (R01 DK108921, R01 DK135032, R01 DK135268, R01 DK136671, R01 DK127270, R01 DK142799, U01 DK127747, P30 DK020572), the Department of Veterans Affairs (I01 BX004444), the Brehm family, and the Anthony family. The Breakthrough T1D Career Development Award was partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.  Pearson was supported by the American Diabetes Association (19-PDF-063). Walker was supported by the NIH (K01 DK133533). Kaufman was supported by the Department of Veterans Affairs (I01 BX004444). Satin was supported by the NIH (R01 DK46409). Arvan was supported by the NIH (R01 DK48280).

Tech transfers/Conflicts of interest: Soleimanpour has received grant funding from Ono Pharmaceutical Co., Ltd. and is a consultant for Novo Nordisk.

Michigan Research Cores: Animal Metabolic, Physiological and Behavioral Phenotyping Core through the Michigan NIH Mouse Metabolic Phenotyping Center; Microscopy, Imaging and Cellular Physiology Core and Islet Core of U-M Diabetes Research Center; U-M Flow Cytometry Core and U-M Advanced Genomics Core.

Paper cited: “Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues,” Science. DOI: 10.1126/science.adf2034

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