Biology subjects

Han, S. M.

Publications and source records attributed to Han, S. M..

5 recordsLinked to original sources

bioRxiv2026

Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories

Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo.

physiology↗

bioRxiv2024

Bisphenol TMC disturbs mitochondrial activity and biogenesis, reducing lifespan and healthspan in the nematode Caenorhabditis elegans

Rising concerns about Bisphenol A (BPA) toxicity have prompted the search for safer alternatives. However, concerns persist regarding the safety of replacements like bisphenol TMC (BPTMC), a rapidly emerging BPA substitute. Utilizing the in vivo model organism Caenorhabditis elegans (C. elegans), whose shared genes mirror human biology, we aim to unveil the potential toxicity of BPTMC on a live animal. C. elegans exposed to 1 mM BPTMC exhibited developmental delays, reduced reproduction, and diminished longevity. Furthermore, an investigation into mortality at various animal stages, oxidative stress, and thermal stress revealed additional compromised toxicity. Notably, exposure to BPTMC resulted in mitochondrial abnormalities, including reduced oxygen consumption, lowered mitochondrial membrane potential, and decreased ATP levels. Additionally, BPTMC increased ROS levels but decreased mitochondrial population. Transcriptome analysis revealed that BPTMC induces alterations in the expression of genes associated with mitochondrial biogenesis. Our findings raise crucial concerns about BPTMC as a safe BPA alternative. The observed widespread toxicity across key life stages suggests a need for further investigation into the potential toxicity of BPTMC on human health and environmental consequences.

pharmacology and toxicology↗

bioRxiv2024

Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging

Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in {gamma}-aminobutyric acid-producing (GABAergic) neurons in Caenorhabditis elegans (C. elegans) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism.

genetics↗

bioRxiv2022

The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner.

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposis sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposis sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. ImportanceKaposis sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces expression of specific viral genes yet does not affect growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rtas ability to redistribute RBP-Jk DNA binding to the virus during reactivation.

microbiology↗

bioRxiv2019

Mapping interactions of microbial metabolites and human receptors

Despite evidence linking the human microbiome to health and disease, the mechanistic details of how the microbiota affects human physiology remain largely unknown. Metabolites encoded by bacteria are expected to play an integral role in the microbiotas effect on its human host. Assigning function to these metabolites is therefore critical to determining the molecular underpinnings of the host-microbe relationship and ultimately developing microbiota inspired therapies. Here we use large-scale functional screening of small molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein coupled receptors (GPCR). This analysis revealed a complex network of metabolite host receptor interactions and guided our identification of multiple microbiota derived agonists of GPCRs associated with diverse biological functions within the nervous and immune systems, among others. Collectively, the metabolite-receptor pairs we uncovered indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.\n\nStatement of SignificanceBacteria residing within the human body have been shown to influence human health. It is likely that physiological responses to the human microbiota are mediated by the collection of small molecules encoded within these bacteria. In this study we use direct functional screening of small molecules produced by individual members of a simplified human microbiota to identify new G protein coupled receptor-metabolite interactions that seek to explain the molecular underpinnings of the microbiotas influence on its human host.

microbiology↗