ESPEYB25 12. Type 2 Diabetes, Metabolic Syndrome and Lipid Metabolism The Metabolic Syndrome (3 abstracts)
12.8. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues
Walker EM , Pearson GL , Lawlor N , Stendahl AM , Lietzke A , Sidarala V , Zhu J , Stromer T , Reck EC , Li J , Levi-D’Ancona E , Pasmooij MB , Hubers DL , Renberg A , Mohamed K , Parekh VS , Zhang IX , Thompson B , Zhang D , Ware SA , Haataja L , Qi N , Parker SCJ , Arvan P , Yin L , Kaufman BA , Satin LS , Sussel L , Stitzel ML & Soleimanpour SA
Science. 2025 Apr 11;388(6743):eadf2034. doi: 10.1126/science.adf2034
Brief Summary: In a series of elegant experiments in mouse models, loss of mitochondrial quality control triggered a retrograde signalling response in β-cells, hepatocytes, and brown adipocytes, impairing cellular identity and maturity.
Comment: Mitochondrial function is vital for maintaining cellular health. However, continuous exposure to environmental stressors makes mitochondria vulnerable to dysfunction. To preserve their integrity, eukaryotic cells have developed a mitochondrial quality control (MQC) mechanism. MQC is a crucial cellular process that ensures the proper function and health of mitochondria. It involves a complex network of mechanisms aimed at preventing the accumulation of damaged mitochondria and maintaining cellular homeostasis. Control mechanisms include mitophagy, genome maintenance, fusion/fission.
Several studies have shown that insulin-producing pancreatic β-cells of patients with T2D have abnormal mitochondria and are unable to generate energy. The current study reveals that mitochondrial dysfunctionin quality control triggers a retrograde signalling pathway that disrupts the identity and maturity of pancreatic beta cells, resulting in reduced β-cell mass not through apoptosis, but through dedifferentiation.
To determine whether impaired MCQ can lead to β-cell failure, researchers developed mouse models lacking key components of this protective machinery. One model had a disruption in mitophagy, impairing the clearance of damaged mitochondria. Another showed mitochondrial DNA depletion, resulting in reduced mitochondrial genetic content. A third model exhibited defective mitochondrial fusion, a process essential for maintaining mitochondrial integrity. Despite targeting different mechanisms, all models revealed the same outcome: a reduction in β-cell mass without detectable cell death. This striking similarity suggests a shared pathway leading to β-cell dedifferentiation or immaturity, rather than apoptosis.
When MQC is impaired, a retrograde signalling pathway is activated Using this pathway, the mitochondria can send signals to the nucleus and change the fate of the cell, leading to cellular dedifferentiation rather than apoptosis in response to mitochondrial damage. Mitochondrial retrograde signaling is triggered by the Integrated Stress Response (ISR) pathway, a cellular defense mechanism activated by mitochondrial dysfunction, oxidative stress, ER stress, nutrient deprivation, and viral infection. To test the importance of the ISR pathway in β-cell maturity, genetically engineered mice in the MQC (via mitophagy)- were treated with ISRIB, a well-established pharmacologic inhibitor of the ISR. ISRIB treatment prevented β-cell mass loss and improved glucose intolerance, suggesting its potential for the treatment or prevention of metabolic disorders
These experiments were repeated in liver cells and brown adipocytes. As in β-cells, mitochondrial quality control loss did not trigger apoptosis but instead reduced mature hepatocyte markers and increased immaturity markers. A similar stress response was activated in brown adipocytes, impairing their function. Inhibiting the retrograde mitochondrial signalling pathway can restore β-cell mass and identity, suggesting that targeting this pathway could be a promising approach for treating metabolic disorders.
Key message: Previously, it was believed that the maintenance of β-cell mass depended on a balance between β-cell replication and apoptosis. It is now recognized that β-cell dedifferentiation is a critical process contributing to β-cell dysfunction in T2D.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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