Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30

Abstract

<jats:title>Abstract</jats:title><jats:p>Mitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in <jats:italic>C. elegans</jats:italic>, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in <jats:italic>C. elegans</jats:italic> that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPR<jats:sup>MT</jats:sup>. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPR<jats:sup>MT</jats:sup>, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.</jats:p><jats:sec><jats:title>SUMMARY</jats:title><jats:p>Mitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.</jats:p></jats:sec>

Quo Vadis Caenorhabditis elegans Metabolomics—A Review of Current Methods and Applications to Explore Metabolism in the Nematode

“…Comparing the levels of TG species between wildtype N2 and fzo-1 mutants, species with less carbons and double bonds were down-regulated, while longer and more unsaturated ones were up-regulated [95]. Mitochondrial dynamics and mitochondrial translation are linked to longevity via the transcription factor HLH-30 [138]. hlh-30 mutants are susceptible to starvation.…”

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

“…Mitochondrial protein translation contributes to mitochondrial proteostasis integrating the mitochondrial and nuclear genomes, which are necessary for the synthesis and assembly of a functional respiratory chain (Couvillion et al, 2016;Taanman, 1999;Wallace, 2010). While defective mitochondrial proteostasis has been linked to neurodegenerative diseases and the control of lifespan (Houtkooper et al, 2013;Liu et al, 2019;Pickles et al, 2018;Sun et al, 2016), there is no indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we substantiate a model where SLC25A1 and MRPL40, two 22q11.2 encoded genes, are necessary for mitochondrial protein translation, proteostasis, and thus synaptic integrity.…”