Biology subjects

Kelly, M. O.

Publications and source records attributed to Kelly, M. O..

3 recordsLinked to original sources

bioRxiv2026

Manganese availability determines insulin sensitivity by enhancing Akt activity

Insulin signaling is a critical determinant of metabolic health, and impairments in insulin action contribute to the development of type 2 diabetes. The kinase Akt is a central mediator of insulin signaling and is required for insulin's suppression of hepatic glucose output. Although the regulation of Akt by the insulin receptor-PI3K pathway is well understood, there are instances in which signaling downstream of Akt is dissociated from proximal insulin signaling, for example in insulin resistance. Nonetheless, little is known about PI3K-independent mechanisms of Akt regulation. Here, we discovered that hepatocyte manganese concentrations are a key determinant of PI3K-independent Akt function in vivo. We further demonstrated that manganese increases Akt's catalytic efficiency, and quantitative phosphoproteomics revealed that manganese and insulin act additively to enhance Akt activity. Moreover, we uncovered that hepatic manganese concentrations fluctuate during fasting and feeding via carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10. This dynamic metal-signaling axis provides a mechanistic link between nutrient status and Akt activation, and suggests a molecular explanation for the glucose-lowering effects of manganese observed in humans. Our findings establish manganese as a physiologically regulated cofactor for Akt and position metal bioavailability as a previously unrecognized layer of insulin signaling control.

physiology↗

bioRxiv2025

Site-1 Protease is a negative regulator of sarcolipin promoter activity

The timed contraction and relaxation of myofibers in tissues such as the heart and skeletal muscle occurs via the tightly regulated movement of calcium ions into and out of the sarcoplasmic reticulum (SR). In skeletal muscle, this phenomenon enables humans to exercise, perform day-to-day tasks, and to breathe. Sarcolipin, a small regulatory protein, prevents calcium ions from entering the SR by binding to and inhibiting SERCA, contributing to myofiber contraction. Disruptions in sarcolipin expression are implicated in the pathophysiology of obesity and musculoskeletal disease. However, the mechanisms regulating sarcolipin expression are not clearly understood. We recently showed that Site-1 Protease (S1P) is a regulator of skeletal muscle function and mass. Here, we report that deleting S1P in mouse skeletal muscle increases sarcolipin expression, without impacting calcium SR flux. In cultured cells, S1P negatively regulates sarcolipin by activating the transcription factor ATF6, which inhibits basal- and calcineurin-stimulated sarcolipin promoter activity. We identified a cAMP response element binding protein (CREB) binding site on the sarcolipin promoter that is necessary for promoter activation, and show that in muscle, CREB binds to the sarcolipin promoter and that this binding is enhanced when S1P is deleted. These discoveries expand our knowledge of S1P biology and the mechanisms controlling calcium regulatory genes.

molecular biology↗

bioRxiv2022

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-{beta}1 target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGF-{beta} signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-{beta} signaling and suggests this protease could be a target for therapeutic intervention in muscle.

molecular biology↗