Biology subjects

Love, A.

Publications and source records attributed to Love, A..

3 recordsLinked to original sources

bioRxiv2026

Remodeling oligodendrocyte lipid metabolism via liver X receptors overcomes inflammatory blockade of remyelination

Multiple sclerosis is characterized by immune-mediated demyelination and inefficient remyelination, owing to impaired differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Inflammatory cytokines within multiple sclerosis lesions inhibit OPC maturation and induce an immune-like phenotype with antigen-presenting properties, but the underlying mechanisms remain poorly defined. Here, we show that inflammation reprograms OPC lipid metabolism, linking altered metabolism to remyelination failure. In cultured rodent OPCs, interferon-{gamma} (IFN-{gamma}) induced a switch from lipid synthesis to utilization, leading to reduced intracellular fatty acid levels and increased dependence on fatty acid oxidation. Transcriptional analyses confirmed similar lipid metabolic changes in OL-lineage cells cultured from human surgical specimens or isolated from mouse models of inflammatory demyelination and human multiple sclerosis lesions. Enhancing lipid availability in OPCs through oleic acid supplementation or inhibition of fatty acid oxidation attenuated immune-like functions and increased differentiation. Pharmacologic activation of liver X receptor (LXR) transcription factors rebalanced lipid metabolism, suppressed immune-like functions, and overcame IFN-{gamma}-induced differentiation blockade in both mouse and human-derived OPCs. In an adoptive transfer-cuprizone mouse model in which inflammation directly impairs remyelination, LXR activation increased mature OL generation and augmented myelin repair. Together, these findings identify lipid metabolic remodeling as a key mechanism by which inflammation impairs OPC differentiation and highlight LXR activation as a therapeutic approach to enhance remyelination in multiple sclerosis.

neuroscience↗

bioRxiv2026

Basal BNIP3/NIX mitophagy is controlled by selective protection of sentinel receptors

Mitochondrial homeostasis is maintained by multiple quality control pathways, including mitophagy, which targets dysfunctional mitochondria for degradation. During receptor-mediated mitophagy, the outer membrane proteins BNIP3 and NIX directly recruit autophagy machinery to the mitochondrial surface, though their precise regulation is still unclear. In recent years, new BNIP3- and NIX-interacting proteins have been identified that influence mitophagic flux. PPTC7 and FBXL4 target BNIP3 and NIX for proteasomal turnover to keep levels of the receptors low, whereas TMEM11 is proposed to spatially control mitophagy by interacting with receptors at active mitophagy sites. However, it is unclear how each of these interactions is controlled and how they interplay with each other. Here, we identify a repressor of mitophagy, ARMC1, which forms a complex with TMEM11, BNIP3, and NIX. During mitophagy activation, ARMC1 dissociates from the complex, freeing the receptors to initiate mitophagy. We find that TMEM11 then acts in an antagonistic relationship with PPTC7, protecting the receptors from proteasomal degradation. Our data are consistent with a two-stage model. At steady state, a population of sentinel receptors is repressed and primed to respond to mitochondrial dysfunction. Once mitophagy is activated, TMEM11 protects BNIP3 and NIX, ensuring a sustained mitophagic response. Our findings provide a framework for understanding how two key regulatory pathways intersect to modulate receptor-mediated mitophagy.

Cell Biology↗

bioRxiv2020

Schengen-pathway controls spatially separated and chemically distinct lignin deposition in the endodermis.

Lignin is a complex polymer precisely deposited in the cell wall of specialised plant cells, where it provides essential cellular functions. Plants coordinate timing, location, abundance and composition of lignin deposition in response to endogenous and exogenous cues. In roots, a fine band of lignin, the Casparian strip encircles endodermal cells. This forms an extracellular barrier to solutes and water and plays a critical role in maintaining nutrient homeostasis. A signalling pathway senses the integrity of this diffusion barrier and can induce over-lignification to compensate for barrier defects. Here, we report that activation of this endodermal sensing mechanism triggers a transcriptional reprogramming strongly inducing the phenylpropanoid pathway and immune signaling. This leads to deposition of compensatory lignin that is chemically distinct from Casparian strip lignin. We also report that a complete loss of endodermal lignification drastically impacts mineral nutrients homeostasis and plant growth.

plant biology↗