Match!

Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

Published on Jun 1, 2020in Journal of Cell Biology8.891
· DOI :10.1083/JCB.201907067
Yasmine J. Liu2
Estimated H-index: 2
(UvA: University of Amsterdam),
Rebecca L. McIntyre1
Estimated H-index: 1
(UvA: University of Amsterdam)
+ 11 AuthorsPallas Yao1
Estimated H-index: 1
(Harvard University)
Sources
Abstract
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.
Figures & Tables
  • References (88)
  • Citations (1)
📖 Papers frequently viewed together
2 Citations
29 Citations
16 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References88
Newest
#1Pan Deng (UMMS: University of Massachusetts Medical School)H-Index: 2
#2Nandhitha Uma Naresh (UMMS: University of Massachusetts Medical School)H-Index: 1
Last. Cole M. Haynes (UMMS: University of Massachusetts Medical School)H-Index: 29
view all 8 authors...
Mitochondria generate most cellular energy and are targeted by multiple pathogens during infection. In turn, metazoans employ surveillance mechanisms such as the mitochondrial unfolded protein response (UPRmt) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPRmt is an adaptive transcriptional program regulated by the transcription factor ATFS-1, which induces genes that promote mitochondrial recovery and innate immunity. The bacterial pathogen Pseudomonas ae...
Source
#1Prasanna V. Ramachandran (BCM: Baylor College of Medicine)H-Index: 4
#2Marzia Savini (BCM: Baylor College of Medicine)H-Index: 2
Last. Meng C. Wang (BCM: Baylor College of Medicine)H-Index: 21
view all 7 authors...
Summary Lysosomes and mitochondria are both crucial cellular organelles for metabolic homeostasis and organism health. However, mechanisms linking their metabolic activities to promote organism longevity remain poorly understood. We discovered that the induction of specific lysosomal signaling mediated by a LIPL-4 lysosomal acid lipase and its lipid chaperone LBP-8 increases mitochondrial s-oxidation to reduce lipid storage and promote longevity in Caenorhabditis elegans. We further discovered t...
6 CitationsSource
#1Yasmine J. Liu (UvA: University of Amsterdam)H-Index: 2
#2Georges E. Janssens (UvA: University of Amsterdam)H-Index: 8
Last. Riekelt H. Houtkooper (UvA: University of Amsterdam)H-Index: 35
view all 10 authors...
The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We ...
4 CitationsSource
#1Yang Li (Ministry of Education)H-Index: 22
#2Yu Zhang (CAS: Chinese Academy of Sciences)H-Index: 33
Last. Chonglin Yang (CAS: Chinese Academy of Sciences)H-Index: 15
view all 14 authors...
Lysosomes are degradation and signaling centers within the cell, and their dysfunction impairs a wide variety of cellular processes. To understand the cellular effect of lysosome damage, we screened natural small-molecule compounds that induce lysosomal abnormality using Caenorhabditis elegans (C. elegans) as a model system. A group of vobasinyl-ibogan type bisindole alkaloids (ervachinines A–D) were identified that caused lysosome enlargement in C. elegans macrophage-like cells. Intriguingly, t...
2 CitationsSource
#1Jeroen Baardman (UvA: University of Amsterdam)H-Index: 4
#2Sanne G. S. Verberk (VU: VU University Amsterdam)H-Index: 1
Last. Jan Van den Bossche (VU: VU University Amsterdam)H-Index: 14
view all 18 authors...
Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory ...
14 CitationsSource
#1Xin-Xuan Lin (KI: Karolinska Institutet)H-Index: 2
#2Ilke Sen (KI: Karolinska Institutet)H-Index: 2
Last. Christian G. Riedel (KI: Karolinska Institutet)H-Index: 13
view all 11 authors...
The ability to perceive and respond to harmful conditions is crucial for the survival of any organism. The transcription factor DAF-16/FOXO is central to these responses, relaying distress signals into the expression of stress resistance and longevity promoting genes. However, its sufficiency in fulfilling this complex task has remained unclear. Using C. elegans, we show that DAF-16 does not function alone but as part of a transcriptional regulatory module, together with the transcription factor...
9 CitationsSource
#1Tomoya Eguchi (UTokyo: University of Tokyo)H-Index: 3
#2Tomoki Kuwahara (UTokyo: University of Tokyo)H-Index: 9
Last. Takeshi Iwatsubo (UTokyo: University of Tokyo)H-Index: 93
view all 11 authors...
Leucine-rich repeat kinase 2 ( LRRK2 ) has been associated with a variety of human diseases, including Parkinson’s disease and Crohn’s disease, whereas LRRK2 deficiency leads to accumulation of abnormal lysosomes in aged animals. However, the cellular roles and mechanisms of LRRK2-mediated lysosomal regulation have remained elusive. Here, we reveal a mechanism of stress-induced lysosomal response by LRRK2 and its target Rab GTPases. Lysosomal overload stress induced the recruitment of endogenous...
21 CitationsSource
#1Duco S. Koenis (UvA: University of Amsterdam)H-Index: 6
#2Lejla Medzikovic (UvA: University of Amsterdam)H-Index: 3
Last. Carlie J.M. de Vries (UvA: University of Amsterdam)H-Index: 31
view all 15 authors...
Summary Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a ...
6 CitationsSource
#1Qian Zhang (CAS: Chinese Academy of Sciences)H-Index: 1
#2Xueying Wu (CAS: Chinese Academy of Sciences)H-Index: 1
Last. Andrew Dillin (University of California, Berkeley)H-Index: 53
view all 7 authors...
Summary The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to perip...
19 CitationsSource
#1Reuben L. SmithH-Index: 7
#2Maarten R. SoetersH-Index: 19
Last. Riekelt H. HoutkooperH-Index: 35
view all 4 authors...
The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The li...
18 CitationsSource
Cited By1
Newest
#1Levi Ali (UMMS: University of Massachusetts Medical School)
#2Cole M. Haynes (UMMS: University of Massachusetts Medical School)H-Index: 29
: In this issue, Liu et al. (2019. J. Cell. Biol.https://doi.org/10.1083/jcb.201907067) find that the inhibition of mitochondrial ribosomes in combination with impaired mitochondrial fission or fusion increases C. elegans lifespan by activating the transcription factor HLH-30, which promotes lysosomal biogenesis.
Source