TY - JOUR
T1 - Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30
AU - Liu, Yasmine J.
AU - McIntyre, Rebecca L.
AU - Janssens, Georges E.
AU - Williams, Evan G.
AU - Lan, Jiayi
AU - van Weeghel, Michel
AU - Schomakers, Bauke
AU - van der Veen, Henk
AU - van der Wel, Nicole N.
AU - Yao, Pallas
AU - Mair, William B.
AU - Aebersold, Ruedi
AU - MacInnes, Alyson W.
AU - Houtkooper, Riekelt H.
N1 - © 2020 Liu et al.
PY - 2020/4
Y1 - 2020/4
N2 - Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates 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 UPRMT, 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 crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.
AB - Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates 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 UPRMT, 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 crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.
KW - Animals
KW - Autophagosomes/drug effects
KW - Basic Helix-Loop-Helix Transcription Factors/genetics
KW - Caenorhabditis elegans Proteins/genetics
KW - Caenorhabditis elegans/metabolism
KW - Gene Ontology
KW - Longevity/genetics
KW - Lysosomes/drug effects
KW - Microscopy, Electron, Transmission
KW - Mitochondria/genetics
KW - Mitochondrial Dynamics/drug effects
KW - Protein Biosynthesis/drug effects
KW - Proteomics
KW - RNA Interference
KW - Reproduction/physiology
KW - Signal Transduction/drug effects
KW - Unfolded Protein Response/drug effects
UR - http://www.scopus.com/inward/record.url?scp=85083022737&partnerID=8YFLogxK
U2 - https://doi.org/10.1083/jcb.201907067
DO - https://doi.org/10.1083/jcb.201907067
M3 - Article
C2 - 32259199
SN - 0021-9525
VL - 219
JO - Journal of cell biology
JF - Journal of cell biology
IS - 6
M1 - e201907067.
ER -