bims-tofagi 2025-10-26 papers

Issue of 2025–10–26
four papers selected by
Michele Frison, University of Cambridge

Trends Endocrinol Metab. 2025 Oct 17. pii: S1043-2760(25)00201-2. [Epub ahead of print]

Mitophagy in the adaptation to pancreatic β cell stress in diabetes.

Elena Levi-D'Ancona, Ava M Stendahl, Belle A Henry-Kanarek, Rebecca K Davidson, Emily M Walker, Scott A Soleimanpour.

Mitophagy is a crucial quality control process that preserves metabolic efficiency by selectively targeting damaged mitochondria for removal. Given the high metabolic demand of pancreatic β cells' insulin secretion, disruption of mitophagy contributes to the mitochondrial dysfunction and β cell failure that are a common feature of both type 1 and type 2 diabetes (T1D and T2D). We review the impact of mitophagy on β cell responses to (patho)physiologic stressors that underlie the development of T1D and T2D. We examine how β cells engage mitophagy in the adaptive response to metabolic, inflammatory, and oxidative damage. We also dissect the importance of ubiquitin- and receptor-mediated mitophagy, methodological advances to quantify mitophagy in β cells, and ongoing efforts to pharmacologically target mitophagy to preserve β cell health and improve glycemic control.

Keywords: CLEC16A; Parkin; islet; mitochondria; ubiquitin

DOI: https://doi.org/10.1016/j.tem.2025.09.009

Exp Mol Med. 2025 Oct 23.

Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease.

Kang-Min Lee, Jihun Kim, Hye Lim Jung, Young Yeon Kim, Jihoon Lee, Yeon-Ju Lee, Eunhee Yoo, Hyi-Seung Lee, Jeanho Yun.

Mitophagy has been implicated in kidney function and related diseases. However, a direct analysis of mitophagy in kidney models, including disease models, remains notably lacking. Here we analyzed mitophagy levels in Drosophila Malpighian tubules, a functional analog of the human kidney, using a transgenic model of the engineered mitophagy reporter mt-Keima. We found that mitophagy is highly active in the major cell types of the Malpighian tubules, including renal stem cells, principal cells and stellate cells. Notably, the suppression of mitophagy by genetic downregulation of mitophagy-related genes, such as ATG5 and ULK1, led to a significant decrease in the secretion function of the Malpighian tubules, suggesting that mitophagy is essential for their proper function. Interestingly, a continuous high-sugar diet, which is used as a model for diabetic kidney disease, caused a reduction in mitophagy levels in principal cells before the development of mitochondrial dysfunction and defective secretion. Importantly, stimulation of mitophagy with the recently developed mitophagy inducer PDE701 rescued both mitochondrial dysfunction and defective phenotypes in a diabetic kidney disease model. Our results highlight the pivotal role of mitophagy in kidney function and suggest that modulating mitophagy could be a potential strategy for treating kidney diseases.

DOI: https://doi.org/10.1038/s12276-025-01558-2

Nat Commun. 2025 Oct 20. 16(1): 8966

Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation.

Yoichi Nibe-Shirakihara, Shinya Honda, Satoko Arakawa, Satoru Torii, Hajime Tajima Sakurai, Hirofumi Yamaguchi, Shigeru Oshima, Ryuichi Okamoto, Michael Lazarou, Hideshi Kawakami, Shigeomi Shimizu.

Golgi membrane-associated degradation (GOMED) is a process that leading to the degradation of proteins that have passed through the trans-Golgi membranes upon Golgi stress. GOMED is morphologically similar to autophagy, but the substrates degraded are different, and they thus have different biological roles. Although the substrate recognition mechanism of autophagy has been clarified in detail, that of GOMED is completely unknown. Here we report that GOMED degrades its substrate proteins selectively via optineurin (OPTN), as we found that the degradation of GOMED substrates is s`uppressed by the loss of OPTN. OPTN binds to K33 polyubiquitin-tagged proteins that have passed through the Golgi, which are then incorporated into GOMED structures for eventual degradation. In vivo, GOMED is known to be involved in the removal of mitochondria from erythrocytes, and in Optn-deficient mice, mitochondria are not degraded by GOMED, resulting in the appearance of erythrocytes containing mitochondria. These findings provide insight into the substrate recognition mechanism of GOMED.

DOI: https://doi.org/10.1038/s41467-025-64400-3

Autophagy Rep. 2025 ;4(1): 2572511

The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.

Mireia Nàger, Mauro Calvoli, Kenneth B Larsen, Asa B Birgisdottir.

The cardiovascular system, consisting of the heart and blood vessels, ensures delivery of oxygen and nutrient-rich blood throughout the whole body. The major cell types include cardiomyocytes, endothelial cells, and vascular smooth muscle cells. Dramatic consequences, sometimes with a deadly outcome, may arise when the activity of cardiovascular cells is compromised. The cardiomyocytes are terminally differentiated cells and thus do not normally regenerate. To sustain the high energy demand of the beating heart, the cardiomyocytes contain a high amount of energy producing mitochondria. Adaptation to metabolic demands is an integral part of cellular homeostasis and involves autophagy. Autophagy is an evolutionary conserved intracellular degradation pathway of cellular constituents. Mitophagy refers to selective degradation of damaged, and thus potentially harmful, mitochondria through autophagy. Both autophagy and mitophagy are widely implicated in physiological and pathological processes within cardiovascular cells. In this review, we highlight studies applying genetic modifications in mouse models to reveal the impact of autophagy and mitophagy on cardiovascular health and disease.

Keywords: Aging; atherosclerosis; development; genetic mouse models; heart failure; myocardial infarction

DOI: https://doi.org/10.1080/27694127.2025.2572511