Rethinking Integration of Environmental and Behavioral Stressors; Back to Energy Homeostasis and Function

SummaryAutophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies have shown that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy. However, the underlying mechanism remains unknown. Here, we report that in amino acid deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During prolonged amino acid starvation, a fraction of p27 is recruited to lysosomes where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 lysosomal localization and activation. p27 binding to LAMTOR1 prevents Ragulator assembly and function and subsequent mTORC1 activation, thereby promoting autophagy. Conversely, upon amino acid withdrawal, p27−/− cells exhibit elevated mTORC1 signaling, impaired lysosomal activity and autophagy, and resistance to apoptosis. This is associated with sequestration of TFEB in the cytoplasm, preventing the induction of lysosomal genes required for lysosomal function. Silencing of LAMTOR1 or mTOR inhibition restores autophagy and induces apoptosis in p27−/− cells. Together, these results reveal a direct, coordinated regulation between the cell cycle and cell growth machineries.

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Methyl Donor Deficiency during Gestation and Lactation in the Rat Affects the Expression of Neuropeptides and Related Receptors in the Hypothalamus

International Journal of Molecular Sciences ◽

10.3390/ijms20205097 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5097 ◽

Cited By ~ 1

Author(s):

Saber Cherif ◽

Pourié ◽

Geoffroy ◽

Julien ◽

Helle ◽

...

Keyword(s):

Growth Retardation ◽

Energy Homeostasis ◽

Peptide Yy ◽

Perinatal Period ◽

Receptor Expression ◽

Critical Periods ◽

Methyl Donors ◽

Methyl Donor ◽

Wide Range ◽

And Function

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.

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Mitochondrial form, function and signalling in aging

Biochemical Journal ◽

10.1042/bcj20160451 ◽

2016 ◽

Vol 473 (20) ◽

pp. 3421-3449 ◽

Cited By ~ 18

Author(s):

Ignacio Amigo ◽

Fernanda M. da Cunha ◽

Maria Fernanda Forni ◽

Wilson Garcia-Neto ◽

Pâmela A. Kakimoto ◽

...

Keyword(s):

Mammalian Cells ◽

Energy Homeostasis ◽

Cell Types ◽

Redox Balance ◽

Whole Body ◽

Model Organisms ◽

Resistance To Stress ◽

Whole Body Metabolism ◽

And Function ◽

Different Characteristics

Aging is often accompanied by a decline in mitochondrial mass and function in different tissues. Additionally, cell resistance to stress is frequently found to be prevented by higher mitochondrial respiratory capacity. These correlations strongly suggest mitochondria are key players in aging and senescence, acting by regulating energy homeostasis, redox balance and signalling pathways central in these processes. However, mitochondria display a wide array of functions and signalling properties, and the roles of these different characteristics are still widely unexplored. Furthermore, differences in mitochondrial properties and responses between tissues and cell types, and how these affect whole body metabolism are also still poorly understood. This review uncovers aspects of mitochondrial biology that have an impact upon aging in model organisms and selected mammalian cells and tissues.

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Metabolic Sensing and the Brain: Who, What, Where, and How?

Endocrinology ◽

10.1210/en.2011-0194 ◽

2011 ◽

Vol 152 (7) ◽

pp. 2552-2557 ◽

Cited By ~ 102

Author(s):

Barry E. Levin ◽

Christophe Magnan ◽

Ambrose Dunn-Meynell ◽

Christelle Le Foll

Keyword(s):

Energy Homeostasis ◽

Distributed Network ◽

Metabolic Substrates ◽

Hepatic Portal Vein ◽

Metabolic Sensing ◽

Hepatic Portal ◽

And Function ◽

The Brain ◽

Local Brain ◽

Brain Barriers

Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis.

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AMPK Regulates the Expression of the Fe-S Cluster Assembly Enzyme (ISCU) and ALAS2, Modulating Cellular Iron Metabolism and Increasing Hemoglobin Synthesis

Blood ◽

10.1182/blood-2018-99-112175 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 851-851

Author(s):

Ping La ◽

Silvia Pires Lourenco ◽

Laura Breda ◽

Stefano Rivella

Keyword(s):

Hydrogen Peroxide ◽

Energy Homeostasis ◽

Cluster Assembly ◽

Ampk Activation ◽

Glucose Starvation ◽

Erythroid Progenitor ◽

Heme Synthesis ◽

Ampk Activity ◽

Murine Erythroleukemia ◽

And Function

Abstract Iron-sulfur (Fe-S) clusters are iron-containing prosthetic groups and enzymatic cofactors. They are strong oxidants when unbound yet essential in many processes like facilitating ATP production in mitochondria, promoting DNA, RNA and protein syntheses during cell proliferation and enhancing DNA repair in antioxidant defense. In particular, Fe-S clusters are indispensable in erythropoiesis, where the majority of physiological iron is utilized and where Fe-S clusters are required for the heme synthesis. Deficient Fe-S cluster synthesis predisposes individual to various diseases, such as cancer, metabolic and neurodegeneration diseases and blood disorders. However, it is unclear how Fe-S cluster synthesis is regulated and coordinates with environmental and developmental needs to prevent oxidative damage. The 5' AMP-activated protein kinase (AMPK) is a kinase activated by oxidative stress and energy starvation and critical for maintaining redox and energy homeostasis. In this study, we investigated the role of AMPK on Fe-S clusters synthesis and function and extended our findings in normal and thalassemic erythroid cells. Through bioinformatic analysis, we found that the Fe-S cluster assembly enzyme (ISCU), a scaffold protein indispensable for Fe-S cluster biogenesis, contains putative AMPK phosphorylation motifs at serine (S) residues 14 and 29 (human numbering). Using the human cell line 293T, we confirmed that AMPK phosphorylates ISCU, while point mutations in these residues prevented this activity. Moreover, AMPK-mediated phosphorylation promoted ISCU binding to 14-3-3s, a family of proteins that, once associate with phosphorylated residues, modulates the stability and function of targeted proteins. Indeed, increased association with 14-3-3s stabilized ISCU proteins, corroborating the observation that AMPK promotes the activity of ISCU proteins. We extended our studies using A549 cells that do not have AMPK activity since they harbor a mutant LKB1 kinase, which is responsible for activating AMPK. By overexpression of wild type (WT)-LKB1 and LKB1 kinase-dead mutant (KDM), we found that only WT-LKB1 restored AMPK activity, binding of ISCU to 14-3-3s and stability of ISCU. Moreover, under hydrogen peroxide incubation and glucose starvation, ISCU protein levels and Fe-S cluster synthesis were both increased only in the presence of LKB1-WT, but not in cells harboring KMD. LKB1-WT overexpressed cells also survived hydrogen peroxide incubation and glucose starvation better than those with KMD. Together, these data suggest that AMPK activation stabilizes ISCU protein and preserves Fe-S cluster synthesis to maintain a healthy redox and energy homeostasis. We then explored the effect of AMPK on Fe-S cluster synthesis in erythropoiesis by using the drug AICAR, an AMPK activator, in murine erythroleukemia (MEL) cells. We found that in MEL cells, AICAR treatment stabilized ISCU, increased Fe-S cluster levels and promoted the synthesis of the aminolevulinic acid synthase 2 (ALAS2) protein, which represents the rate-limiting enzyme in erythroid heme synthesis. Furthermore, this was associated with increased heme and globin chain synthesis, with a trend in increasing β-globin mRNA and proteins more than α-globin. We further confirmed these observations in Human Umbilical Cord Blood-Derived Erythroid Progenitor (HUDEP-2) and CD34+ cells derived from peripheral blood isolated from both healthy individuals and ß-thalassemic patients. In these cells, we found that AMPK upregulation by AICAR administration not only increased ALAS2 expression and erythroid heme levels, but also enhanced the synthesis of both a- and ß-globin chains, though with a preference for increasing β-globin levels. Analysis using specimens from thalassemic mice is in progress. In conclusion, our work demonstrates that under redox and energetic stress, activated AMPK phosphorylates and stabilizes ISCU protein, thereby enhancing Fe-S cluster synthesis and maintaining their function. Moreover, AMPK activation with AICAR treatment increases erythroid heme synthesis and hemoglobin expression. Given that AMPK is the major kinase that responds to oxidative and energetic cues, our work provides a mechanistic explanation for how erythropoiesis responds to energy starvation and redox stress as well as a potential novel therapeutic target to treat blood and metabolic disorders. Disclosures Rivella: Ionis Pharmaceuticals, Inc: Consultancy; MeiraGTx: Other: SAB; Protagonist: Consultancy; Disc Medicine: Consultancy.

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Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.673977 ◽

2021 ◽

Vol 8 ◽

Author(s):

Nimesha Tadepalle ◽

Elena I. Rugarli

Keyword(s):

Lipid Droplets ◽

Energy Homeostasis ◽

Signaling Cascades ◽

Spastic Paraplegia ◽

Hereditary Spastic Paraplegias ◽

The Central Nervous System ◽

Experimental Findings ◽

And Function ◽

Hsp Genes ◽

Dying Back

Hereditary spastic paraplegias (HSPs) are genetically heterogeneous conditions caused by the progressive dying back of the longest axons in the central nervous system, the corticospinal axons. A wealth of data in the last decade has unraveled disturbances of lipid droplet (LD) biogenesis, maturation, turnover and contact sites in cellular and animal models with perturbed expression and function of HSP proteins. As ubiquitous organelles that segregate neutral lipid into a phospholipid monolayer, LDs are at the cross-road of several processes including lipid metabolism and trafficking, energy homeostasis, and stress signaling cascades. However, their role in brain cells, especially in neurons remains enigmatic. Here, we review experimental findings linking LD abnormalities to defective function of proteins encoded by HSP genes, and discuss arising questions in the context of the pathogenesis of HSP.

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Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.757305 ◽

2021 ◽

Vol 9 ◽

Author(s):

T. Bradley Willingham ◽

Peter T. Ajayi ◽

Brian Glancy

Keyword(s):

Skeletal Muscle ◽

Energy Homeostasis ◽

Single Cells ◽

Muscle Cells ◽

Cell Types ◽

Current Data ◽

Skeletal Muscle Cells ◽

Form And Function ◽

Mitochondrial Heterogeneity ◽

And Function

Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.

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Abstract P373: The Occurrence Of Neurovascular And Adipose Neuropathy In The Genetically Diverse Het3 Mouse With Aging

Circulation Research ◽

10.1161/res.129.suppl_1.p373 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Jake Willows ◽

Morganne Robinson ◽

Harrison Cyr ◽

Gargi Mishra ◽

Peter Reifsnyder ◽

...

Keyword(s):

Adipose Tissue ◽

Blood Vessels ◽

Energy Homeostasis ◽

Advanced Age ◽

Brown Adipocytes ◽

Subcutaneous White Adipose Tissue ◽

Age Related ◽

Neural Communication ◽

And Function ◽

Related Mortality

Energy homeostasis and adipose tissue metabolism are regulated in large part through peripheral sympathetic nerve innervation of metabolically important tissues and organs. This neural communication from the brain to adipose tissues results in release of the neurotransmitter norepinephrine that regulates energy expenditure through modulation of lipolysis, adipogenesis, ‘browning’ (development of brown adipocytes in white adipose depots), and non-shivering thermogenesis. Subcutaneous white adipose tissue (scWAT) is an energy storing tissue that is highly plastic, responding to metabolic need by changing mass and cellularity, as well as responding to challenges (including cold temperature, exercise, fasting) by modifying neural activity and metabolism. Within scWAT lies a dense bed of nerves and blood vessels that are integrated closely, and in large part, rely on one another to function properly. Even if not directly innervating the blood vessels themselves (as is the case with capillaries), neurites that appear to innervate single adipocytes use these blood vessels as scaffolding to traverse the tissue. We have recently demonstrated that under pathological conditions (obesity and aging), scWAT innervation decreases through a process termed ‘adipose neuropathy’. With advanced age the small fiber peripheral nerve endings in adipose die back, including reducing contact with adipose-resident blood vessels (as observed previously in the C57BL6/J mouse). This likely poses a physiological challenge for metabolism and for vascular or adipose tissue health and function. For this work, we compared C57BL6/J mice with the more genetically diverse HET3 mouse model, established for the NIA’s Intervention Testing Program to more accurately represent the variability of age-related mortality/morbidity. We investigated incidence of peripheral neuropathy with aging (skin, scWAT muscle) as well as changes to the neurovascular supply of scWAT across several ages in both males and females. We also investigated the anti-aging drug Rapamycin as a potential means to prevent or reduce adipose neuropathy. We found that HET3 mice display a reduced neuropathy phenotype compared to inbred C56BL6/J mice. Importantly, the nerve die-back around blood vessels was not observed in the HET3 model. However, male HET3 mice did reveal neuropathic phenotypes by 62wks of age, characterized by decreased mechanoreception in hind paw skin, reduced NMJ occupation, and decreased expression of the Schwann cell marker Sox10 in scWAT. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126wks) when they began to show stronger phenotypes than males (excluding Sox10 analysis.) Despite its success as a longevity treatment in mice, rapamycin had little to no effect on reducing or preventing the onset of adipose neuropathy.

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The mineralocorticoid receptor: a new player controlling energy homeostasis

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0033 ◽

2013 ◽

Vol 15 (2) ◽

Cited By ~ 1

Author(s):

Emmanuelle Kuhn ◽

Marc Lombès

Keyword(s):

Mineralocorticoid Receptor ◽

Energy Homeostasis ◽

Adipocyte Differentiation ◽

Therapeutic Potential ◽

Control Point ◽

Brown Adipocyte ◽

Transgenic Mouse Models ◽

Electrolyte Homeostasis ◽

Potential Impact ◽

And Function

AbstractNumerous studies have demonstrated the interaction that exists between adipocyte differentiation, energy balance and factors involved in fluid and electrolyte homeostasis, such as the renin-angiotensin-aldosterone system. More specifically, a potential impact of aldosterone on the function of several organs implicated in the control of energy homeostasis, such as adipose tissue, liver, skeletal muscle or pancreas, has been recently described. In addition, the mineralocorticoid receptor (MR, NR3C2), a transcription factor, was shown to play a crucial role on white and brown adipocyte differentiation and function, mediating the effects of both mineralocorticoid and glucocorticoid hormones on adipose tissues. Transgenic mouse models as well as pharmacological inactivation of MR signaling provided compelling evidence that MR is an important control point for energy homeostasis. Herein, we review recent findings on the involvement of aldosterone but also of MR on energy metabolism and discuss the therapeutic potential of manipulating MR signaling for the management of metabolic disorders in humans.

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