Biology subjects

Yoval-Sanchez, B.

Publications and source records attributed to Yoval-Sanchez, B..

4 recordsLinked to original sources

bioRxiv2026

Lipid mediated ER-stress contributes to the pathogenesis of mitochondrial myopathies

Mitochondrial diseases are a heterogeneous group of genetic disorders caused by impaired oxidative phosphorylation (OxPhos). When skeletal muscle is predominantly affected, they are defined as primary mitochondrial myopathies. Although the genetic causes of mitochondrial myopathies and the resulting bioenergetic impairments are well established, the metabolic drivers behind progressive muscle dysfunction remain poorly defined. This gap in knowledge may contribute to the lack of effective treatments for these disorders. OxPhos defective muscle initiates a metabolic response coordinated by systemic signals which invokes the mobilization of fatty acids from white adipose tissue despite muscle inability to fully oxidize fatty acids due to OxPhos impairment. Here, we show that in human patients with mitochondrial disease and mice with OxPhos defective muscle, increased fatty acid mobilization from white adipose tissue leads to ectopic lipid accumulation and lipotoxicity in skeletal muscle. We find an increase in very long chain ceramides which are mechanistically linked to chronic ER stress, phosphorylation of eIF2, and activation of ATF4 signaling. We propose that Ph-eIF2-mediated attenuation of global protein synthesis and ATF4-initiated atrophy pathways contribute to muscle wasting and weakness. Importantly, inhibition of de novo synthesis of ceramides with myriocin reduces ER stress and improves muscle proteostasis, body weight, and motor functions in a conditional COX10 KO mouse model of mitochondrial myopathy. Together, these findings highlight altered lipid metabolism as a contributor of mitochondrial myopathy pathogenesis and identify lipid-mediated stress pathways that can be targeted therapeutically.

Molecular Biology↗

bioRxiv2025

Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance

Resistance to Brutons tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates NDUFA4L2 to inhibit mitochondrial respiration, thereby blocking mitochondria-dependent ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, these findings establish BRG1 as a central regulator of therapy resistance and provide a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.

cancer biology↗

bioRxiv2025

Rescuing Ischemic Brain Injury by Rewiring Mitochondrial Electron Flow

Mitochondrial metabolic flux alterations are critical drivers of acute ischemia-reperfusion (IR) brain injury. Reverse electron transfer (RET), defined as the upstream flow of electrons from the quinone pool to complex I, is a major source of pathological reactive oxygen species (ROS) under stress conditions. In an in vivo brain IR model, oxygen deprivation induces the buildup of RET-supporting substrates, with glycerol 3-phosphate identified as the dominant contributor in addition to succinate. Rapid oxidation of these substrates by brain mitochondria upon reoxygenation drives massive ROS production, while also leading to over-reduction and dissociation of the complex I flavin mononucleotide (FMN) cofactor. The resulting FMN-deficient complex I becomes catalytically impaired, unable to oxidize NADH or to produce ROS. To mitigate RET and preserve complex I function, we used transgenic mice xenotopically expressing alternative oxidase (AOX). This enzyme bypasses complexes III and IV by directly oxidizing the reduced quinone pool and passing electrons onto molecular oxygen. AOX expression did not alter complex I abundance, supercomplexes assembly, or basal respiration rates, but effectively diverted electrons from the quinone pool, decreasing RET flux via complex I and limiting ROS generation during IR. For the first time we showed that AOX expression and attenuation of RET preserved complex I FMN binding, suppressed oxidative stress, and conferred neuroprotection in vivo. Our findings reveal a novel strategy for rewiring mitochondrial electron flux to mitigate initial IR brain injury, highlighting modulation of the quinone pool by AOX as a potential therapeutic strategy for IR.

biochemistry↗

bioRxiv2022

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Mitochondrial defects are a common hallmark of familial and sporadic forms of amyotrophic lateral sclerosis (ALS). However, the origin of these defects, including reduced pyruvate metabolism and reduced oxygen consumption, is poorly understood. These metabolic functions are regulated in specialized endoplasmic reticulum (ER) domains in close contact with mitochondria, called mitochondrial-associated ER membranes (MAM). Recently it has been shown that MAM domains are disrupted in ALS, but the connection between MAM dysregulation and mitochondrial defects in ALS cells remains unclear. Using human embryonic stem cell (ESC)-derived motor neurons (hMNs) and mouse models with ALS-pathogenic mutations in superoxide dismutase 1 (SOD1), we found that the glycolytic deficiency in ALS is a direct consequence of the progressive disruption of MAM structure and function that hinders the use of glucose-derived pyruvate as a mitochondrial fuel and triggers a shift in mitochondrial substrates from pyruvate to fatty acids. This glycolytic deficiency, over time, induces significant alterations in mitochondrial electron flow and in the active/dormant (A/D) status of complex I in spinal cord, but not in brain. These data agree with a role for MAM in the maintenance and regulation of cellular glucose metabolism and suggest that MAM disruption in ALS could be the underlying cause of the bioenergetic deficits observed in the disease.

molecular biology↗