Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans

Abstract

Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

“…Although some stresses such as dietary restriction are known to trigger the UPR mit and autophagy in parallel in worms (Bennett et al, 2017) and the UPR mit was recently linked to DR and its downstream effectors in Drosophila (Borch Jensen, Qi, Riley, Rabkina, & Jasper, 2017), the impact of UPR mit on autophagy independently of stress has never been described. In order to address this question, we generated an ubl‐5 mutant expressing LGG‐1::GFP to monitor autophagy levels in vivo .…”

The role of Rsv1 in the transcriptional regulation of genes involved in sugar metabolism for long‐term survival

“…The gluconate shunt, the first reaction of which is mediated by Gcd1, provides NADPH and ribose 5phosphate through the pentose phosphate pathway [30]. Although the genetic regulation of the NADPHgenerating pathways has not been well-studied under nutrient starvation, some studies have described the relationship between genes involved in the pentose phosphate pathway and lifespan, suggesting that the transcription levels of pentose phosphate pathway genes are actively adjusted to maintain cell viability [35][36][37]. Based on our additional ChIP-Seq and RNA-Seq results, we found that Rsv1 directly represses the transcription of idn1, gnd1, hxk2, and gcd1, a set of genes involved in the glucose shunt and pentose phosphate pathway, for up to 6 h of glucose starvation (Fig.…”

SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death

“…A variety of cellular stresses, including lysosomal dysfunction, cause activation of TFEB [32][33][34] . As SARS 3a causes lysosomal damage, we looked to see if SARS 3a induced TFEB nuclear translocation by separating the cytosolic and nuclear fraction from 293T cells and detecting endogenous TFEB.…”