Biology subjects

Poothong, J.

Publications and source records attributed to Poothong, J..

2 recordsLinked to original sources

bioRxiv2026

Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans

Mild reductions in mitochondrial electron transport chain (ETC) capacity paradoxically extend organismal lifespan, a conserved phenomenon termed mitohormesis. While the mitochondrial unfolded protein response (UPRmt) and AMP-activated protein kinase (AMPK) are both established regulators of this process, whether distinct mitochondrial lesions converge on a single, unified survival mechanism remains unclear. By systematically dissecting the genetic architectures governing longevity in Caenorhabditis elegans, we demonstrate that targeted RNAi knockdown of Complex I (nuo-6) and Complex IV (cco-1) subunits activates fundamentally divergent downstream pathways. Both structural defects robustly induce the UPRmt, yet lifespan extension from Complex I impairment highly dependent on the UPRmt master regulator ATFS-1 while bypassing the AMPK ortholog AAK-2. Conversely, Complex IV-mediated longevity operates independent of ATFS-1 but requires AAK-2-driven metabolic reprogramming. Pharmacological intervention with metformin - a Complex I inhibitor and AMPK activator - further exposed complex-specific vulnerabilities: metformin markedly suppressed the longevity phenotype of nuo-6;aak-2 mutants, whereas in cco-1;aak-2 animals it produced a trend toward lifespan extension that appeared independent of AAK-2. Together, these findings challenge the view of mitohormesis as a uniform response, revealing instead that cells engage specialized, molecularly tailored retrograde signaling networks to govern lifespan and respond to pharmacological interventions.

cell biology↗

bioRxiv2020

Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum

Factor VIII (FVIII) is the coagulation factor deficient in hemophilia A, which is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low level secretion. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress and induces apoptosis. Importantly, little is known about the factors that cause protein misfolding and aggregation in metazoans. Here we identified intrinsic and extrinsic factors that cause FVIII to form aggregates in the ER. We show that FVIII forms amyloid-like fibrils within the ER upon increased FVIII synthesis or inhibition of glucose metabolism. Significantly, FVIII amyloids can be dissolved upon restoration of glucose metabolism to produce functional secreted FVIII. Two ER chaperones and their co-chaperones, BiP and CANX/CRT, promote FVIII solubility in the ER, where the former is also required for disaggregation. A short aggregation motif in the FVIII A1 domain (termed Aggron) is necessary and sufficient to seed {beta}-sheet polymerization and BiP binding to this Aggron prevents amyloidogenesis. Our findings provide novel insight into mechanisms that limit FVIII secretion and ER protein folding in general and have implication for ongoing hemophilia A gene therapy clinical trials. Key Points- FVIII forms amyloid aggregates in the ER that are dissolved in a chaperone- and glucose-dependent manner to produce secreted active FVIII. - A short amino acid sequence in the A1 domain causes {beta} sheet polymerization and ER chaperone BiP binding to this site prevents aggregation.

molecular biology↗