R. Luke Wiseman

The paper identifies how pathogenic MFN2 variants cause mtDNA release into endosomes and mitochondrial-derived vesicles, triggering inflammation and myopathy, and suggests a therapeutic strategy using integrated stress response activation.

This study shows that AA147, a metabolically activated proteostasis regulator, reduces TH17 cell differentiation by degrading RORgammat and IRF4, and dampens effector cytokine responses across T cell subsets.

This paper shows that maternal antiviral history before pregnancy enhances offspring immunity through IgG in milk, which is transferred via FcRn and provides protection beyond weaning.

This study identifies ATAD3A as a structural link between mtDNA replication and mitochondrial fission by forming membrane tethers that coordinate these processes.

This paper introduces DM, a detergent that reduces air-water interface artifacts in cryo-EM, improving reconstruction quality and particle stability.

This study shows that IXA4 inhibits SLC33A1, causing ER hyperoxidation and activating IRE1/XBP1s signaling, which reduces viability of KEAP1-deficient lung cancer cells.

The paper identifies two compounds that activate the HRI pathway, improving mitochondrial function in MFN2-deficient cells.

This study identifies potent PDIA1 inhibitors that block NLRP3 inflammasome activity without significant cellular toxicity, offering a strategy to treat diseases involving hyperactive NLRP3.

This study shows that inhibiting PGK1 with CBR-470-2 reduces NF-κB signaling by increasing methylglyoxal, which inactivates NF-κB proteins.

This study identifies AA263 analogs that enhance ER proteostasis by targeting ER protein disulfide isomerases, correcting protein misfolding in disease models.

AA147 reduces oligodendrocyte loss and demyelination in a mouse model of MS by activating ATF6 and NRF2 pathways, improving clinical symptoms and microglia activation.

This study shows that activating XBP1s reduces disease severity in CMT1B models by mitigating ER stress and mutant protein toxicity in Schwann cells.

This study shows that pharmacologic activation of ISR kinases HRI or GCN2 prevents mitochondrial fragmentation in disease models.

The paper identifies a novel homozygous MFN2 variant R334K linked to a lethal neonatal disorder and shows it causes severe mitochondrial dysfunction, confirmed through functional studies and Drosophila modeling.

This study shows methylglyoxal, a glycolytic metabolite, covalently inactivates the NLRP3 inflammasome by forming crosslinks, thereby reducing inflammation.

The paper identifies the integrated stress response (ISR) as the primary signaling pathway activated by mitochondrial proteostasis stress using gene set profiling in Perturb-seq datasets.

This study reports the cryo-EM structure of DELE1's C-terminal fragment, showing its oligomerization and role in activating the integrated stress response.

The paper determines the cryo-EM structure of yeast Lon protease (PIM1) and shows it forms a hexamer similar to bacterial and human Lon proteases, with unique structural features and a dispensable yeast-specific insertion.

This study determines the cryo-EM structures of human LONP1 to elucidate the molecular mechanism of its proteolytic activation and regulation.

This study shows that forcing dimerization between ATF6f and XBP1s enhances UPR activity, reducing protein aggregation in neurodegenerative disease models.

This study shows ATF6 is essential for human cone photoreceptor development and demonstrates that ATF6 activators can restore cone growth in patient-derived retinal organoids.

This study identifies IGF2 as a disease modifier that reduces intracellular protein aggregates by promoting their extracellular disposal in Huntington's disease models.

This study determines the structure of AFG3L2, revealing how its unique features influence enzymatic activity and disease-related mutations.

The paper determines the cryo-EM structure of Y. pestis Lon protease during substrate processing, revealing a distinct hand-over-hand translocation mechanism unique to the HCLR clade.

The paper presents the first atomic structure of the mitochondrial inner membrane AAA+ protease YME1, revealing its mechanism of substrate processing and translocation.