Mitochondrial defects contribute to Type 2 Diabetes

Introduction

More than 35 million people in the United States have Type 2 Diabetes (T2D), and approximately 100,000 of them die from T2D each year, making it the eighth leading cause of death in the country. T2D is one of the most common metabolic disorders, characterized by elevated levels of blood glucose which causes damage to multiple tissues including heart, vasculature, eyes, kidneys and nerves. The main mechanisms that cause T2D are β-cell dysfunction in the pancreatic islets; insulin resistance, where cells in the body do not respond to insulin; and disruption in the balance between glucagon and insulin, leading to elevated blood sugar levels. Risk factors that increase the chances of getting T2D are family history, age, ethnicity and genetics. Lifestyles also play an important role, putting people that are overweight, lack physical activity, and have a poor diet at a higher risk of developing T2D.

Mitochondrial defects contribute to Type 2 Diabetes

Defects in mitochondrial function in cells is a new paradigm being suggested as a mechanism for T2D [1,2,3]. Mitochondria are the powerhouse of the cell, producing high energy molecules such as ATP. Mitochondrial dysfunction can cause problems in different tissues. In insulin-producing pancreatic β-cells, mitochondrial defects lead to structural abnormalities and impaired ATP production. Skeletal muscle from individuals with T2D exhibits reduced mitochondrial ATP production. Defective mitochondria can also cause decreased ATP synthesis in visceral adipose tissue and liver.

Mitochondrial quality control (QC) is impaired in β-cells leading to T2D

In response to various physiological signals or external stimuli, a sophisticated mitochondrial QC mechanism has evolved, encompassing key processes like mitochondrial biogenesis, function, and mitophagy (internal digestion of mitochondria) to stabilize mitochondrial functions [4]. Mitochondrial QC is impaired in pancreatic β-cells in T2D. Human islets isolated from T2D donors show reduced mitochondrial DNA content and decreased expression of mitochondrial-encoded RNAs specifically in β-cells. Despite these reductions, mitochondrial mass remains unchanged, as indicated by stable expression of mitochondrial proteins. Additionally, β-cells from T2D donors exhibit impaired mitochondrial turnover. These defects are not observed in non-β-cells indicating β-cell-specific impairments in mitochondrial quality control is a contributing factor in T2D pathogenesis.

Defects in mitochondrial QC induce loss of β-cell identity and function

Impaired QC leads to loss of β-cells differentiation state in T2D. A recent finding is that in T2D, insulin-producing β-cells undergo dedifferentiation, lose their specialized identity, and transition into progenitor-like cells [5]. Studies of various models of diabetes in mice show upregulation of undifferentiated phenotype genes and down-regulation of β-cell maturation markers, associated with impaired mitochondrial fusion and respiration. Pathway analysis showed disruptions in insulin secretion and mitochondrial lipid metabolism, along with activation of developmental pathways. In addition, loss of mitochondrial QC triggers β-cell chromatin remodeling, altering gene expression and promoting β-cell dedifferentiation. Gene enrichment analysis indicates disruptions in mitophagy, lysosomal transport, and glucose metabolism are a result of chromatin remodeling [7]. These findings suggest that mitochondrial retrograde signaling drives chromatin modifications that promote β-cell dysfunction and dedifferentiation in T2D. These findings suggest that mitochondrial dysfunction may drive β-cell dedifferentiation, contributing to T2D progression.

Defective mitochondrial quality control induces an integrated stress response (ISR)

The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial ISR triggers diverse metabolic responses contributing to β-cell dedifferentiation and immaturity. Murine diabetic models demonstrated up-regulated ISR genes and similar findings are observed in human β-cells. Results from several studies establish mitochondrial retrograde signaling through the ISR as a key mechanism driving β-cell dysfunction in T2D.

Blocking retrograde signaling in mitochondria restores β-cell mass and maturity in vivo

Mitochondrial retrograde signaling refers to communication sent to the nucleus from the mitochondria [2,3,6]. Biological signaling usually proceeds from (external) stimuli affecting nuclear gene expression, to RNA and protein expression. These signals affect nuclear gene expression and lead to changes in cellular responses, helping the cell adapt to new conditions.

Mitochondrial IRS instigates pathologic retrograde signaling. Blocking mitochondrial retrograde signaling through the integrated stress response (ISR) restores β-cell mass and maturity in vivo. Murine models show that a small molecule inhibitor of ISR, restored β-cell maturity markers, and decreased dedifferentiation markers in isolated islets. The therapy prevented β-cell mass loss and improved glucose tolerance without affecting insulin sensitivity. These findings establish ISR-mediated mitochondrial retrograde signaling as a direct regulator of cell maturity and identity in metabolic tissues.

Summary

Mitochondrial QC is a key regulator of cellular identity and maturity across multiple metabolic tissues, including pancreas β-cells, hepatocytes, and brown adipocytes, as well as primary human islets. Mitochondrial dysfunction triggers retrograde signaling through the integrated stress response (ISR), which drives transcriptional changes, chromatin remodeling, and cellular dedifferentiation. Notably, these effects are reversible, as ISR inhibition restores β-cell mass, maturity, and function.

Mitochondria have previously been considered secondary players in metabolic disorders, but recent research highlights their primary role in regulating cell fate. Reduced mitochondrial gene expression were evident in β-cells from prediabetic individuals, suggesting that mitochondrial dysfunction may precede and contribute to T2D pathogenesis. These findings position mitochondrial QC as a critical determinant of cell identity in metabolic tissues and a potential therapeutic target for T2D and related disorders.

References

1.Galicia-Barcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebai, A., Siddigi, H,. Uribe, KB., Ostolaza, H., and Martin, C. Pathophysiology of Type 2 Diabetes Melllitus..Int J Mol Sci 21:6275, 2020.:
2.Walker, E.M., Pearson G.L., Soleimanpour, S.A.,plus 27 authors. Retrograde mitochondrial signaling governs the identity and maturity of metabolic diseases. BioRxiv doi: doi.org/10.1101/2022.08.02.502357
3.Chae, S., Ahn, B.Y., Park, K.S. and 5 more authors. A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways. Science Signaling 6:rs4, 2013.
4. Liu, B.-H., Xu, C-Z., Liu, Y.,Lu,Z.-L.,Fu, T.Y., Li, G.-R., Deng, Y.,Luo, G.-Q., Ding,S., Li, N. and and Geng, Q. Mitochondrial quality control in human health and disease. Military Medical Research 11:2024.
5.Patel, S. and Remedi, S. Loss of β-cell identity and dedifferentiation, not an irreversible process? Front Endocrinol 15:141447, 2024
6.Liu, Z. and, Butow, R. Mitochondrial retrograde signaling. Annu Rev Genet 40:159, 2006
7.Tian, Y., Garcia, G., Bian, Q.,Steffen, K.K., Joe, L., Wolff, S., Meyer, B.J., and Dillin, A. Mitochondrial stress induces chromatin reorganization to promote longevity and UPRmt
Cell. 165:1197, 2016

About Marin Biologic Laboratories

Our Recent Publication/Meeting Presentation on Gene Therapy

1.  Development of a Pharmacokinetic (PK) Mouse Serum GLP ELISA for an Anti–CD19–AntiCD3 Diabody
bioRxiv 2025.03.19.644217; doi: https://doi.org/10.1101/2025.03.19.644217
2. Cell-Based Potency Assay for Anti-CD3-Anti-CD19 Diabody. bioRxiv 2025.04.15.648836v1 https://www.biorxiv.org/content/10.1101/2025.04.15.648836v1
3.  American Society of Hematology (ASH) Annual Meeting 2024.
Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity  Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

Comprehensive Assay Solutions for In Vitro and Cell Based Potency Assays and Pharmacokinetics Studies- Our Expertise

With 30 years of expertise in cell culture, cell-based assays, and preclinical/clinical PK/PD analysis, we specialize in offering assay services essential for a wide variety of therapeutic drug development programs, preclinical studies, IND/BLA applications, and commercialization. Our comprehensive services include both preclinical non-GLP and GLP assays, as well as non-GMP and GMP assays, providing critical support throughout the entire development pipeline.

Watch the following video and explore our latest presentation on the development and validation of potency and pharmacokinetic (PK) assays for AAV vectors, highlighting innovative methodologies and industry-leading expertise.

 

 

Download the full presentation: Development of Custom Cell Based and In vitro Potency and Pharmacokinetics (PK) Assays for AAV vectors- Marin biologic Laboratories

 

Development of Cell-Based Potency Assays: Case Studies and Blogs from Marin Biologic Laboratories (MarinBio)

 

Drug Discovery & Development Assays Offered by Marin Biologic Laboratories (MarinBio)