Biology subjects

Lu, M.-J.

Publications and source records attributed to Lu, M.-J..

4 recordsLinked to original sources

bioRxiv2025

A Covalent PFKL Activator Suppresses Tumor Growth

Glycolysis fuels vital cellular functions and its dysregulation is implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, presents a key vulnerability for developing targeted anticancer agents but remains challenging due to metabolic heterogeneity and resistance. Here, we developed a first-in-class covalent phosphofructokinase-1 liver type (PFKL) activator that induces metabolic imbalance coupled to delivery of a cytotoxic payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate (EDC) site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL and destabilize cell metabolism. We introduce EDCs as a new delivery mechanism analogous to antibody-drug conjugates but differentiated by selective covalent targeting of intracellular proteins.

biochemistry↗

bioRxiv2025

Cahn-Hilliard dynamical models for condensed biomolecular systems

Biomolecular condensates create dynamic subcellular compartments that alter systems-level properties of the networks surrounding them. One model combining soluble and condensed states is the Cahn-Hilliard equation, which specifies a diffuse interface between the two phases. Customized approaches required to solve this equation are largely inaccessible. Using two complementary numerical strategies, we built stable, self-consistent Cahn-Hilliard solvers in Python, MATLAB, and Julia. The algorithms simulated the complete time evolution of condensed droplets as they dissolved or persisted, relating critical droplet size to a coefficient for the diffuse interface in the Cahn-Hilliard equation. We applied this universal relationship to the chromosomal passenger complex, a multi-protein assembly that reportedly condenses on mitotic chromosomes. The fully constrained Cahn-Hilliard simulations yielded dewetting and coarsening behaviors that closely mirrored experiments in different cell types. The Cahn-Hilliard equation tests whether condensate dynamics behave as a phase-separated liquid, and its numerical solutions advance generalized modeling of biomolecular systems.

systems biology↗

bioRxiv2022

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

SLC25A51 imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AMLs dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition. Statement of significanceThis investigation describes an approach to directly modulate the tricarboxylic acid cycle as a potential vulnerability in oxidative tumors. Using AML models, the work is an inaugural look into SLC25A51s role supporting oxidative mitochondrial metabolism and identifies SLC25A51 levels as a potential marker for stratification of AML.

cancer biology↗

bioRxiv2021

A Positive Regulatory Feedback Loop Between 1 EKLF/ KLF1 and TAL1/SCL2 Sustaining the Erythropoiesis

The erythroid Kruppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf-/-) mouse embryos, we have identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with molecular/cellular analysis of mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tall gene promoter in combination with in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates Tall gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors that sustains the mammalian erythropoiesis.

cell biology↗