Biology subjects

Walder, K. R.

Publications and source records attributed to Walder, K. R..

5 recordsLinked to original sources

bioRxiv2025

From iPSCs to NPCs to cortical neurons: bioenergetic, neuronal, and calcium signaling phenotypes in bipolar disorder with and without familial mitochondrial disease

BackgroundPsychiatric disorders frequently accompany primary mitochondrial diseases (PMDs), implicating mitochondrial dysfunction as a shared biological substrate for psychiatric vulnerability. To determine how familial mitochondrial risk influences neuronal development in bipolar disorder (BD), we generated induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and cortical neurons (CNs) from three healthy controls (CT), three patients with BD, and three patients with BD and a family history of mitochondrial disease (BD-FMD). MethodsAcross differentiation, we assessed mitochondrial function (ATP production, mitochondrial membrane potential, ROS generation, cytosolic cell-free mtDNA), metabolomic signatures, calcium imaging, and neuronal electrophysiological activity through multi-electrode arrays (MEA). ResultsBD neurons uniquely exhibited pronounced hyperexcitability in comparison to CT and BD-FMD groups. The BD-FMD group displayed prolonged mitochondrial calcium transients, altered membrane potential, and aberrant ROS, in comparison to CT and BD, consistent with a sustained energetic deficit. Metabolomic profiling revealed distinct pathway enrichments in BD and BD-FMD, indicating divergent bioenergetic adaptations to mitochondrial burden. ConclusionsOur findings reveal that familial mitochondrial liability actively reshapes neuronal differentiation and function, producing distinct trajectories of mitochondrial performance, calcium signaling, and network excitability. These results suggest that mitochondrial dysfunction in BD is not a secondary byproduct of illness, but a mechanistic contributor to altered neuronal energetics and communication. Together, these findings delineate how inherited mitochondrial vulnerability reshapes neuronal excitability and metabolism, revealing bioenergetic phenotypes that may inform precision stratification and therapeutic targeting in BD.

neuroscience↗

bioRxiv2025

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

Bipolar disorder (BD) is increasingly recognized as a disorder with both mitochondrial dysfunction and heightened inflammatory reactivity, yet their contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. Additionally, a Bioactive Flavonoid Extract (BFE) was explored as a potential therapeutic, demonstrating partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.

neuroscience↗

bioRxiv2023

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance

Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. "Diversity Outbred in Australia (DOz)" is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscles contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focussing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complimentary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin resistant mouse muscle, and palmitate induced insulin resistant myotubes demonstrated potent insulin action restoration, potentially via up-regulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems level analysis by identifying potential therapeutics for insulin resistance.

systems biology↗

bioRxiv2022

Class IIa HDACs reprogram mitochondrial metabolism to inhibit apoptosis and ferroptosis in response to lipotoxicity

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

cell biology↗

bioRxiv2022

Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimers disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (A{beta}42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases A{beta}42, which is increased from adipose tissue of obese mice and is associated with higher plasma A{beta}42. Increasing circulating A{beta}42 levels in non-obese mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating levels of the closely related A{beta}40 isoform were increased. Administration of an A{beta} neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, A{beta} neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that A{beta}42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to A{beta}42 inhibited mitochondrial function. These data reveal a role for systemic A{beta}42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimers disease could be effective in combating obesity-induced heart failure.

physiology↗