Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Zhang, Yue; Lanjuin, Anne; Chowdhury, Suvagata Roy; Mistry, Meeta; Silva-García, Carlos Giovanni; Weir, Heather J.; Lee, Chia-Lin; Escoubas, Caroline C.; Tabakovic, Emina; Mair, William

doi:10.7554/elife.49158

Cited by 98 publications

(109 citation statements)

References 66 publications

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“…It is well‐established that changes in mitochondrial function can signal throughout organisms to extend C. elegans lifespan 70 . In addition, neuronal AMPK mediates longevity in C. elegans and is interconnected with other metabolic pathways that affect mitochondrial morphology 72 . Our results complement each of these findings and suggest that the PMF may be the source change that leads to signaling downstream to affect physiology.…”

Section: Discussionsupporting

confidence: 74%

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

et al. 2020

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Mitochondria are organelles that provide energy to cells. Matching energy supply with energy demand is coordinated through various processes and is critical for cellular adaptation and survival under changing conditions. Therefore, an organism's health depends not only on mitochondrial energy production, but on the ability to sense metabolic status and the ability of mitochondria to signal appropriately to use that energy. 1,2 The mechanisms through which cellular energy-related signaling can occur likely depend on the electrochemical gradient across the mitochondrial inner membrane (IM). Mitochondrial respiration results in a proton gradient across the IM known as the protonmotive force (PMF). Ultimately, respiratory complexes of the electron transport chain (ETC) convert chemical energy into electrical potential energy by pumping protons across the IM, creating this gradient. The PMF can then be consumed at ATP synthase,

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Section: Discussionsupporting

confidence: 74%

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

et al. 2020

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“…4a). Alternatively, the 5′-AMPactivated protein kinase (AMPK) limits TORC1 activity and protein synthesis when ATP levels are low 21,22 .…”

Section: Atfs-1 Mediates a Mitochondrial Expansion Program During Devmentioning

confidence: 99%

UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

Shpilka

Yang

et al. 2021

Nat Commun

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As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPRmt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation.

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“…4a). Alternatively, the 5’ AMP-activated protein kinase (AMPK) limits TORC1 activity and protein synthesis when ATP levels are low 17,18 .…”

Section: Mainmentioning

confidence: 99%

UPR^mtscales mitochondrial network expansion with protein synthesis via mitochondrial import

Shpilka

Yang

et al. 2020

Preprint

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As organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPRmt activity throughout development due to increased accumulation within mitochondria. The insulin-like signaling-TORC1 and AMPK pathways affected UPRmt activation in a manner that correlated with protein synthesis. Manipulation to increase protein synthesis caused UPRmt activation. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial accumulation of ATFS-1. However, ATFS-1 with a dysfunctional MTS constitutively increased UPRmt activity independent of TORC1 function. Lastly, expression of a single protein with a strong MTS, was sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation. Mitochondrial network expansion is attenuated once ATFS-1 can be imported.

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Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Cited by 98 publications

References 66 publications

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

UPR^mtscales mitochondrial network expansion with protein synthesis via mitochondrial import

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Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Cited by 98 publications

References 66 publications

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance inC. elegans

UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

UPRmtscales mitochondrial network expansion with protein synthesis via mitochondrial import

Contact Info

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Resources

About

UPR^mtscales mitochondrial network expansion with protein synthesis via mitochondrial import