Biology subjects

Zhang, I. X.

Publications and source records attributed to Zhang, I. X..

3 recordsLinked to original sources

bioRxiv2022

Differential roles of beta-cell IP3R and RyR ER Ca2+ channels in ER stress-induced alterations of beta-cell Ca2+ homeostasis

Pancreatic beta cells maintain glucose homeostasis by secreting pulses of insulin in response to a rise in glucose. Pulsatile secretion occurs due to glucose-induced oscillations in beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca2+, and ER stress can lead to ER Ca2+ depletion, beta-cell dysfunction and an increased risk of type 2 diabetes. To determine the effects of tunicamycin-induced ER stress on ER inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) and their involvement in subsequent Ca2+ dysregulation, INS-1 832/13 cells and primary mouse islets were treated with tunicamycin. This increased RyR1 mRNA and potentiated RyR-mediated Ca2+ signaling without affecting RyR2 mRNA. TM treatment also enhanced IP3R function, while it decreased IP3R1 and IP3R3 mRNA. Stress reduced ER Ca2+, triggered oscillations in cytosolic Ca2+ under subthreshold glucose conditions, and increased apoptosis; these changes were prevented by cotreatment with the RyR1 inhibitor dantrolene. In contrast, inhibiting IP3Rs with xestospongin-C failed to suppress the cytosolic Ca2+ oscillations due to tunicamycin treatment and did not protect beta cells from tunicamycin-induced apoptosis, although xestospongin-C inclusion prevented ER Ca2+ depletion. Taken together, changes in RyR1 function were shown to play a critical role in ER stress induced Ca2+ dysfunction and beta-cell apoptosis.

physiology↗

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↗

bioRxiv2017

The effect of macromolecular crowding on single-round transcription by E. coli RNA polymerase

Biological reactions in the cellular environment differ physicochemically from those performed in dilute buffer solutions due to, in part, slower diffusion of various components in the cellular milieu, increase in their chemical activities, and modulation of their binding affinities and conformational stabilities. In vivo transcription is therefore expected to be strongly influenced by the crowdedness of the cell. Previous studies of transcription under macromolecular crowding conditions have focused mainly on multiple cycles of RNAP-Promoter associations, assuming that the association is the rate-determining step of the entire transcription process. However, recent reports demonstrated that late initiation and promoter escape could be the rate-determining steps for some promoter DNA sequences. The investigation of crowding effects on these steps under single-round conditions is therefore crucial for better understanding of transcription initiation in vivo. Here, we have implemented an in vitro transcription quenched-kinetics single-molecule assay to investigate the dependence of transcription reaction rates on the sizes and concentrations of crowders. Our results demonstrate an expected slowdown of transcription kinetics due to increased viscosity, and an unexpected enhancement in transcription kinetics by large crowding agents (at a given viscosity). More importantly, the enhancements dependence on crowder size significantly deviates from hard-sphere model (scaled-particle theory) predictions, commonly used for description of crowding effects. Our findings shed new light on how enzymatic reactions are affected by crowding conditions in the cellular milieu.

biochemistry↗