bims-mecosi 2023-10-15 papers

Issue of 2023‒10‒15
three papers selected by
Verena Kohler, Umeå University

Discov Med. 2023 Oct;35(178): 653-663

Role of Mitochondrial Dysfunction in Cellular Lipid Homeostasis and Disease.

Mitochondria-associated membranes (MAMs) play a significant role in multiple cellular processes including lipid metabolism and neuronal survival. Fatty acids constitute 80% of the dry mass of the brain and are vital for life. Apart from mitochondrial β-oxidation, fatty acids are metabolized in part by peroxisomes to regulate the generation of acyl Coenzyme A and adenosine triphosphate (ATP). Ablation of mitochondria and its associated genes tether endoplasmic reticulum (ER)-Mitochondria contact and results in loss of function leading to aberrant lipid metabolism. Additionally, an increase in reactive oxygen species (ROS) levels along with free radicals' generation may lead to alteration in the integrity of membrane phospholipids, proteins, and DNA. Hence, it is critical to understand the effect of structural and functional aspects of mitochondria on lipid homeostasis. This review explains the role of mitochondrial dysfunction in lipid metabolism and its impact on various neurodegenerative diseases and metabolic disorders.

Keywords: lipid metabolism; mitochondria dysfunction; neurodegenerative disease

DOI: https://doi.org/10.24976/Discov.Med.202335178.64

FEBS J. 2023 Oct 09.

S-acylation: an orchestrator of the life cycle and function of membrane proteins.

Francisco S Mesquita, Laurence Abrami, Arthur Samurkas, F Gisou van der Goot.

S-Acylation is a covalent post-translational modification of proteins with fatty acids, achieved by enzymatic attachment via a labile thioester bond. This modification allows for dynamic control of protein properties and functions in association with cell membranes. This lipid modification regulates a substantial portion of the human proteome and plays an increasingly recognized role throughout the lifespan of affected proteins. Recent technical advancements have propelled the S-acylation field into a "molecular era," unveiling new insights into its mechanistic intricacies and far-reaching implications. With a striking increase in the number of studies on this modification, new concepts are indeed emerging on the roles for S-acylation in specific cell biology processes and features. After a brief overview of the enzymes involved in S-acylation, this viewpoint focuses on the importance of S-acylation in the homeostasis, function, and coordination of integral membrane proteins. In particular, we put forward the hypotheses that S-acylation is a gatekeeper of membrane protein folding and turnover and a regulator of the formation and dynamics of membrane contact sites.

Keywords: ERAD; S-acylation; deacylation; folding; membrane-contact-sites; palmitoylation; protein turnover

DOI: https://doi.org/10.1111/febs.16972

Sci Rep. 2023 Oct 12. 13(1): 17257

Increased Ca2 + transport across the mitochondria-associated membranes by Mfn2 inhibiting endoplasmic reticulum stress in ischemia/reperfusion kidney injury.

Shun Wang, Xiaohong Sang, Suhua Li, Wenjun Yang, Shihan Wang, Haixia Chen, Chen Lu.

Renal ischemia/reperfusion (I/R) injury, which leads to acute kidney injury (AKI), is a major cause of morbidity and mortality in a variety of clinical situations. This study aimed to investigate the protective role of Mfn2 during renal I/R injury. Overexpression of Mfn2 in NRK-52E rat renal tubular epithelial cells and rats, then we constructed hypoxia reoxygenation (H/R) cells and I/R rat model. Apoptosis, ROS, ATP, Ca2+ levels in cells and rats, as well as renal tissue and functional injury in rats were detected respectively. Endoplasmic reticulum (ER) stress was further examined in cells and rats. The morphological changes of mitochondria-associated ER membranes (MAMs) were also detected. Mfn2 expression is reduced in H/R-treated NRK-52E cells and renal tissue of I/R rats. At the cellular level, overexpression of Mfn2 promoted cell proliferation, inhibited cell apoptosis, attenuated mitochondrial damage and Ca2+ overload, and ER stress. In addition, Mfn2 also restored the MAMs structure. In vivo experiments found that overexpression of Mfn2 could improve renal function and alleviate tissue injury. Concomitant with elevated Mfn2 expression in the kidney, reduced renal cell apoptosis, restored mitochondrial function, and reduced calcium overload. Finally, ER stress in rat kidney tissue was alleviated after overexpression of Mfn2. These results reveal that Mfn2 contributes to ER stress, mitochondrial function, and cell death in I/R injury, which provides a novel therapeutic target for AKI.

DOI: https://doi.org/10.1038/s41598-023-44538-0