Biology subjects

Satin, L. S.

Publications and source records attributed to Satin, L. S..

4 recordsLinked to original sources

bioRxiv2025

Effects of calreticulin deficiency and myeloproliferative neoplasm (MPN)-linked mutation on cellular calcium signaling

Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone with low affinity calcium binding sites in its C-terminal domain. This region is altered by somatic mutations in the CRT gene (CALR), which drive a subset of myeloproliferative neoplasms (MPN). Perturbations in ER calcium storage and signaling are reported for the MPN type I mutant, CRTDel52, and are linked to disease pathogenesis. Using recombinant CRT proteins, we found similar low affinity calcium binding characteristics for wild-type CRT and CRTDel52, as determined by isothermal titration calorimetry (ITC). Residues 340-349, conserved in both wild-type CRT and CRTDel52, contribute to binding. Furthermore, ER and cytosolic calcium levels and store-operated calcium entry (SOCE) were comparable in CRT knockout (CRT-KO) cells reconstituted with wild-type CRT or CRTDel52. Notably, the CRT-KO induces expression of multiple ER proteins known to contain low affinity calcium binding sites or regulate ER calcium levels. Overall, these findings indicate that CRTDel52 retains at least some low affinity calcium binding capacity and that CRT-deficiency induces compensatory cellular changes that maintain ER calcium homeostasis. SummaryPathogenic CRTDel52 retains at least partial low-affinity calcium-binding capacity. Additionally, live-cell imaging and flow cytometry with ratiometric calcium probes indicate that ER and cytosolic calcium levels, as well as store-operated calcium entry (SOCE), are comparable in CRT-deficient cells rescued with either wild-type CRT or CRTDel52.

cancer biology↗

bioRxiv2022

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes and metabolic dysfunction-associated steatotic liver disease, yet the consequences of impaired mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across multiple metabolic tissues. Surprisingly, we demonstrate that defects in the mitochondrial quality control machinery, which we observe in pancreatic {beta} cells of humans with type 2 diabetes, cause reductions of {beta} cell mass due to dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted deficiency anywhere in the mitochondrial quality control pathway (e.g., genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in {beta} cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signaling in vivo restores {beta} cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues and may be a promising target to treat or prevent metabolic disorders.

cell biology↗

bioRxiv2020

Mitophagy protects beta cells from inflammatory damage in diabetes

Inflammatory damage contributes to {beta}-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in {beta}-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent {beta}-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient {beta}-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased {beta}-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human {beta}-cell apoptosis. Thus, mitophagy promotes {beta}-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent {beta}-cell failure in diabetes and may be beneficial in other inflammatory conditions.

cell biology↗

bioRxiv2020

Chop/Ddit3 depletion in β-cells alleviates ER stress and corrects hepatic steatosis

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic {beta} cells is enhanced, which can lead to proinsulin (ProIns) misfolding that aggravates endoplasmic reticulum (ER) homeostasis in {beta} cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in {beta} cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved {beta} cells in high fat diet (HFD) fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine {beta} cells confers therapeutic benefits. First, we show that Chop deletion in {beta} cells alleviates {beta} cell ER stress and delays glucose-stimulated insulin secretion (GSIS) in HFD fed mice. Second, importantly, {beta} cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary to Chop deletion modulates glucose-induced islet Ca2+ oscillations. Finally, using state-of-the-art GLP1-conjugated Chop AntiSense Oligonucleotides (GLP1-Chop ASO), we demonstrated that the Chop deletion induced GSIS change is a long term complex event in {beta} cells. In summary, our results demonstrate that Chop depletion in {beta} cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D.

physiology↗