Basal re-esterification finetunes mitochondrial fatty acid utilization

Sharma, Anand K.; Wang, Tongtong; Othman, Alaa; Khandelwal, Radhika; Balaz, Mioslav; Modica, Salvatore; Zamboni, Nicola; Wolfrum, Christian

doi:10.1016/j.molmet.2023.101701

Cited by 12 publications

(17 citation statements)

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“…These data reveal ATGL-1-dependent TAG lipolysis, which is likely elevated in ncl-1 KD and reduced in tif-1A KD animals, to be an instigator of mitochondrial stress. Notably, increased lipolysis of TAGs and the subsequently increased flux of fatty acids into mitochondria were recently linked to alterations in mito-homeostasis and elevated oxygen consumption rate (OCR) 57 . We next measured OCR levels in ncl-1 and tif-1A KDs at the age with the strongest difference in their TAG expenditure (AD12, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In this context, tif-1A and rpoa-2 KDs exhibited increased TAG levels, indicating slower TAG expenditure similar to the dynamics observed in dauer larvae, while TAG levels in ncl-1 KD suggest accelerated TAG catabolism. Such differences in TAG mobilization are likely influencing the levels of FAs that are released from TAGs and further processed by mitochondria dictating oxygen consumption rate (OCR) and expression of mitochondrial homeostasis genes 57 . Consistently, we found OCR to be elevated in ncl-1 KD nematodes, while it was lowered in tif-1A KD animals.…”

Section: Discussionmentioning

confidence: 99%

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Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Sharifi,

Chaudhari,

Martirosyan

et al. 2024

Nat Commun

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Ribosome biogenesis is initiated by RNA polymerase I (Pol I)-mediated synthesis of pre-ribosomal RNA (pre-rRNA). Pol I activity was previously linked to longevity, but the underlying mechanisms were not studied beyond effects on nucleolar structure and protein translation. Here we use multi-omics and functional tests to show that curtailment of Pol I activity remodels the lipidome and preserves mitochondrial function to promote longevity in Caenorhabditis elegans. Reduced pre-rRNA synthesis improves energy homeostasis and metabolic plasticity also in human primary cells. Conversely, the enhancement of pre-rRNA synthesis boosts growth and neuromuscular performance of young nematodes at the cost of accelerated metabolic decline, mitochondrial stress and premature aging. Moreover, restriction of Pol I activity extends lifespan more potently than direct repression of protein synthesis, and confers geroprotection even when initiated late in life, showcasing this intervention as an effective longevity and metabolic health treatment not limited by aging.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Sharifi,

Chaudhari,

Martirosyan

et al. 2024

Nat Commun

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“…Recently, Sharma et al demonstrated that inhibition of DGAT1 and 2 increased basal AMPK activation in brown adipocytes and that this was associated with an increase in AMP levels that occurred during uncoupling 44 . While we cannot completely rule out changes in energy charge that occur due to direct effects of FFAs on mitochondrial uncoupling 44 or inhibition of ATP synthase 35 , 45 , our data support a model in which AMPK senses the cellular environment in adipocytes through multiple mechanisms to maintain energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Direct effects of adipocyte lipolysis on AMPK through intracellular long-chain acyl-CoA signaling

Rahman,

Butcko,

Songyekutu

et al. 2024

Sci Rep

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Long-chain acyl-CoAs (LC-acyl-CoAs) are important intermediary metabolites and are also thought to function as intracellular signaling molecules; however, the direct effects of LC-acyl-CoAs have been difficult to determine in real-time and dissociate from Protein Kinase A (PKA) signaling. Here, we examined the direct role of lipolysis in generating intracellular LC-acyl-CoAs and activating AMPK in white adipocytes by pharmacological activation of ABHD5 (also known as CGI-58), a lipase co-activator. Activation of lipolysis in 3T3-L1 adipocytes independent of PKA with synthetic ABHD5 ligands, resulted in greater activation of AMPK compared to receptor-mediated activation with isoproterenol, a β-adrenergic receptor agonist. Importantly, the effect of pharmacological activation of ABHD5 on AMPK activation was blocked by inhibiting ATGL, the rate-limiting enzyme for triacylglycerol hydrolysis. Utilizing a novel FRET sensor to detect intracellular LC-acyl-CoAs, we demonstrate that stimulation of lipolysis in 3T3-L1 adipocytes increased the production of LC-acyl-CoAs, an effect which was blocked by inhibition of ATGL. Moreover, ATGL inhibition blocked AMPKβ1 S108 phosphorylation, a site required for allosteric regulation. Increasing intracellular LC-acyl-CoAs by removal of BSA in the media and pharmacological inhibition of DGAT1 and 2 resulted in greater activation of AMPK. Finally, inhibiting LC-acyl-CoA generation reduced activation of AMPK; however, did not lower energy charge. Overall, results demonstrate that lipolysis in white adipocytes directly results in allosteric activation of AMPK through the generation of LC-acyl-CoAs.

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“…Diacylglycerol O‐acyltransferase 1 and 2 (DGAT1/DGAT2) are two enzymes that catalyze the last reaction of triglyceride synthesis (Chitraju et al , 2019 ; Sharma et al , 2023 ). In humans, DGAT1 seems to be indispensable for dietary lipid absorption (Haas et al , 2012 ).…”

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confidence: 99%

“…P ‐values (mentioned in the graphs) were calculated by group‐wise comparisons by a two‐tailed student t ‐test. (D) Seahorse extracellular flux analysis to measure the effect of D1 + 2i on the oxygen consumption rate (OCR) as a readout of cellular FAO (Sharma et al , 2023 ). HepG2 cells (upper panel, 30,000 cells per well) or in vitro differentiated brown adipocytes (lower panel, replated on day 5 of differentiation at the density of 10,000 cells per well) were cultured on 96‐well extracellular flux measurement culture plates.…”

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confidence: 99%

DGAT inhibition at the post‐absorptive phase reduces plasma FA by increasing FA oxidation

Sharma,

Wolfrum

2023

EMBO Mol Med

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Basal re-esterification finetunes mitochondrial fatty acid utilization

Cited by 12 publications

References 50 publications

Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Direct effects of adipocyte lipolysis on AMPK through intracellular long-chain acyl-CoA signaling

DGAT inhibition at the post‐absorptive phase reduces plasma FA by increasing FA oxidation

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