Biology subjects

Schuettpelz, J.

Publications and source records attributed to Schuettpelz, J..

2 recordsLinked to original sources

bioRxiv2024

SLC25A46 is in contact with lysosomes and plays a role in mitochondrial cholesterol homeostasis

Mitochondrial morphology reflects the dynamic equilibrium between fusion and fission events, controlled by cellular signaling. A cytoprotective response known as stress-induced mitochondrial hyperfusion (SIMH) is triggered by nutrient starvation and we show that the outer mitochondrial membrane protein SLC25A46 is required for this response. To unravel the cellular mechanisms involved, we conducted transcriptomic analysis on control human fibroblasts and SLC25A46 knock-out cells. Our analysis revealed a remarkable divergence in the transcriptional profile of proteins associated with lysosomal function and cholesterol binding and synthesis. Further investigations using live-cell imaging validated the presence of SLC25A46 at the majority of mitochondria-lysosome contact sites. Since mitochondria-lysosome contacts are linked to cholesterol transport, we investigated the involvement of SLC25A46 in cholesterol trafficking. The SLC25A46 knock-out cell line exhibited a decrease in mitochondrial cholesterol content and distinct alterations were observed in the pattern of cholesterol trafficking compared to control. Cholesterol supplementation in the SLC25A46 knock-out cell line rescued the mitochondrial fragmentation phenotype and restored the SIMH response, suggesting a role for SLC25A46 in maintaining mitochondrial cholesterol homeostasis. Summary blurbThe mitochondrial outer membrane protein SLC25A46 is required for SIMH triggered by nutrient starvation, localizes to lysosome contact sites and is involved in mitochondrial cholesterol homeostasis

cell biology↗

bioRxiv2022

SLC25A46 localizes to sites of mitochondrial fission and fusion and loss of function variants alter the oligomerization states of MFN2 and OPA1

Mutations in SLC25A46, coding for an outer mitochondrial membrane protein, underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology, but the precise role of the protein remains unknown. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three different variants (p.T142I, p.R257Q, p.E335D) introduced into the null background. Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to impaired cellular proliferation and striking abnormalities in mitochondrial cristae ultrastructure that were not rescued by expression of the pathogenic variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and at tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually all fission/fusion events were demarcated by the presence of an SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins indicating that it is present at interorganellar contact sites important for lipid exchange. Consistent with this, SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.

cell biology↗