Searle, K. | bioRxiv Science

bioRxiv2026

NLRX1 is an essential, druggable regulator of mitochondrial permeability transition

The molecular composition of the mitochondrial permeability transition pore (mPTP) remains contested, and several efficacious mPTP inhibitors act through undefined, cyclophilin D (CypD)-independent targets. Using two structurally distinct chemotypes of optimised, brain-penetrant mPTP inhibitors as chemical probes, we applied affinity-based chemoproteomics to identify the mitochondrial NOD-like receptor NLRX1 as their shared target. Both chemotypes bind NLRX1, and binding potency across a compound series tracks mPTP-inhibitory activity. Using CRISPR-Cas9-edited human cells and Nlrx1-/- mouse tissues, we show that NLRX1 is required for normal calcium-induced mPTP opening: its loss raises the calcium threshold for pore opening and its overexpression lowers it, independently of CypD. NLRX1 associates with postulated mPTP components, including ATP synthase and the adenine nucleotide translocase, in a compound-sensitive manner, and sustains mitochondrial protein homeostasis over longer timescales. The lead compound, GSK900, is orally bioavailable, brain-penetrant, and active in an mPTP-sensitive neurological injury model. These findings, converging with recent genetic studies, establish NLRX1 as an essential, CypD-independent regulator of mitochondrial permeability transition and provide brain-penetrant chemical tools to interrogate this biology.

cell biology↗

bioRxiv2020

Small scale variability in soil moisture drives infection of vulnerable juniper populations by invasive forest pathogen

The oomycete plant pathogen, Phytophthora austrocedri, is an aggressive killer of cypress trees causing severe mortality of Chilean cedar (Austrocedrus chilensis) in Argentina since the 1940s and now common juniper (Juniperus communis s.l.) in the UK. Rapid mortality of key UK juniper populations was first observed in the early 2000s; the causal agent of mortality was confirmed as P. austrocedri in 2012 and the pathogen has now been widely detected - but is not ubiquitous - in juniper populations across Scotland and England. Although juniper has a broad distribution across the northern hemisphere, the UK incidence of P. austrocedri remains the only confirmed infection of juniper populations globally. Juniper is an important species for biodiversity, so it is imperative to understand the abiotic and biotic drivers of emergent P. austrocedri infection to inform detection, containment and conservation strategies to manage juniper populations across the full extent of its range. As management of UK juniper populations is primarily conducted at a local level, we investigated field scale drivers of disease - in three, geographically separate populations with different infection histories. Variation in the proportion of juniper showing symptoms - discoloured or dead foliage - was measured using stratified sampling across along key environmental gradients within each 100-hectare population, including juniper density identified from aerial imagery. Potential predictors of infection included altitude, slope, distance to nearest watercourse, soil moisture (mean percentage volumetric water content), area of red deer browsing damage and area of commonly associated vascular plant species. We assessed support in the data for alternative models explaining the spatial distribution of P. austrocedri symptoms using full subset covariate selection and Deviance Information Criteria (DIC). Despite differences in environmental gradients and infection histories between populations, area of juniper symptomatic for P. austrocedri increased with waterlogging, increasing with soil moisture in sites where soils had higher peat or clay contents, and decreasing with proximity to watercourses where sites had shallower, sandier soils. These results are consistent with key drivers identified at both local and landscape scale in Chilean cedar. Our approach enables identification of site-specific disease management strategies including prioritisation of inspections in microsites with high soil moisture and promoting conservation measures such as creation of sites for natural regeneration in drier microsites to minimise pathogen spread and maximise the resilience of existing juniper populations.

ecology↗