Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine Sparing in the Mitochondria

Abstract

Anabolic and catabolic signaling mediated via mTOR and AMPK (AMP-activated kinase) have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although glutamine is known to activate mTOR, whether and how differential mitochondrial utilization of glutamine impinges on mTOR signaling has been less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signaling/pathways through the AMPK-PGC1α/SIRT1–peroxisome proliferator-activated receptor α (PPARα) axis and negatively regulate glutamine metabolism via the tricarboxylic acid cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signaling and regulates lipogenesis, autophagy, and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to α-ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

“…The circulating concentration of AKG, which decreases with ageing [ 8 ] but increases upon fasting [ 9 ], hypoxia [ 11 ] and exercise [ 10 , 44 ], reflects changes in metabolic flux. Interestingly, the changes in circulating AKG levels reported in previous studies on HF metabolites are inconsistent.…”

“…AKG (α-KG), also known as 2-oxoglutarate (2-OG), is an important intermediate in the TCA cycle between succinyl-CoA and isocitrate and regulates adenosine triphosphate (ATP) production as a crucial point in the anaplerotic reaction [ 7 ]. The circulating AKG concentration was found to decrease with ageing [ 8 ] and is elevated under fasted states [ 9 ], after acute exercise [ 10 ] and resistance exercise [ 11 ], and in HF [ 5 , 6 ]. Clinical studies showed that a high circulating AKG level was associated with HF severity (NYHA classification) and adverse outcome in acute HF (AHF) and chronic HF (AHF) patients [ 12 , 13 ].…”

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

“…Our work is the first to observe increased gdh transcript levels associated with the presence of Wolbachia infection. This Such correlation coupled with (1) the predicted presence of amino acid uptake transporters and their associated metabolic pathways (glutamine included) in the genome of distinct Wolbachia strains [ 23 , 24 ], and (2) the observation that SIRT-4 (known to directly inhibit GDH activity) protein levels peak in a nutrient rich environment [ 69 ], together suggests that Wolbachia might be acting as a nutrient scavenger, depleting the host of key nutrients. This depletion might then mimic a calorie restriction scenario driving the downregulation of host sirt-4 , and leading to upregulation of its direct target gdh in order to compensate for such energetic loss.…”

“…Previous work has shown that yeast-enriched diet resulted in reduced ovarian Wolbachia titer via TORC1, in which the upstream effectors remain to be discovered [ 42 ]. Additionally, exciting recent work has shown that GDH inhibition via SIRT-4 leads to mTORC1 activation [ 69 ]. As such, by linking previous work to our data presented here, we propose that the observed reduction in Wolbachia density detected in flies reared on a yeast-enriched diet is potentially the result of the upstream effector SIRT-4.…”

Continuous variable responses and signal gating form kinetic bases for pulsatile insulin signaling and emergence of resistance

“…Others and we have found that metabolic cues under fasting conditions elicit anticipatory molecular mechanisms to mount an efficient fed response ( 49 – 51 ). In this context, we have unraveled that pulsatile 0.1 nM insulin rewires signaling dynamics in response to 1 nM inputs.…”