As an essential organelle in the cell, the lysosome is responsible for digestion and recycling of intracellular components, storage of nutrients, and pH homeostasis. The lysosome is enclosed by a special membrane to maintain its integrity, and nutrients are transported across the membrane by numerous transporters. Increasing evidence suggests that the nutrient-sensitive transcription factors (TFs): transcription factors EB (TFEB), p53, and members of the FOXO family, regulate lipophagy during fasting and that the nuclear receptor and co-receptor family members: PPARa and PGC1a, link lipophagy to other pathways involved in lipid catabolism. Moreover, the signals that trigger lipophagy may start from within the lysosome. The lysosome is emerging as a sensor of cellular metabolic cues. The capacity of mTORC1 to associate to the lysosomal membrane, along with the recent observation that members of the extracellular signal regulated kinase (ERK) pathway localize to autophagosomes, are both indications that the lysosomal/ autophagy pathway is a critical regulator of cellular metabolism. This observation raises new important biological questions on the role of the lysosome in regulating energy metabolism and suggests that genetic and environmental factors affecting lysosomal homeostasis can influence whole-body metabolism. This concept may have a profound impact on the development of novel therapeutic strategies for a variety of human diseases, ranging from genetic disorders such as lysosomal storage diseases (LSDs) to the more common metabolic processes associated with aging and obesity. Using a combination of genetics, metabolomics, biochemistry, and immunocytochemistry, Folick et al. explored the molecular mechanisms by which lysosomal LIPL-4 activation regulates aging in C. elegans. They show that worms overexpressing LIPL-4 live substantially longer than normal worms and produce increased amounts of several bioactive lipids, notably the fatty acid oleoylethanolamide(OEA). In addition to OEA, other lipids or metabolites could act as diffusible signals between different organelles to orchestrate coordinated cellular responses. Unbiased metabolomic profiling is a promising discovery tool to decipher the mechanisms underlying many human metabolic diseases. This approach would also help to identify the elusive ligands for many nuclear receptors. Ultimately, modulations of bioactive lipids could be a therapeutic strategy for a wide range of human metabolic disorders and age-related diseases.
Micropropagation of Madagascar periwinkle (Catharanthus roseus)
Lysosome an orchestrating, metabolic sensor during fasting
1. Lysosome an orchestrating, metabolic sensor during fasting
Light towards longevity…
Karmveer Yadav
Ph.D. Scholar_ABC_NDRI
2. Structure of Lysosome
Lysosomes function in autophagy, the process that breaks down cellular
components to allow cell survival and homeostasis in the face of starvation.
Carmine Settembre et. al nature reviews | molecular cell biology volume 14 | may 2013
3. Promoting Health and Longevity through Diet:
Luigi Fontana et. al. Cell 161, March 26, 2015
12. This approach would also help to identify the elusive ligands for many nuclear
receptors.
Ultimately, modulations of bioactive lipids could be a therapeutic strategy for a
wide range of human metabolic disorders and age-related diseases.
13. Carmine Settembre et. al., The EMBO Journal VOL 31 | NO 5 | 2012
Self-regulation of the lysosome via mTOR and TFEB
14.
15. TFEB links lipophagy to β-oxidation via nuclear receptors
Carmine Settembre et. Al. Trends in Cell Biology December 2014, Vol. 24, No. 12
17. Different metabolites converge on pathways that regulate autophagy
and aging
S. Schroeder et al. Microbial Cell | April 2014 | Vol. 1 No. 4
18. Alejo Efeyan et al Trends in Molecular Medicine (2012) 1–10
Making sense of amino acid sensing
The lysosome is now recognized as a key intracellular organelle involved in
mTORC1 activation by amino acids and growth factors.
19. Amino acid sensing
Robert T. Abraham, Science 347, 128 (2015)
Many cancer cell lines have increased mTORC1 activity and show a high
dependence on Gln for growth. Therefore, Gln-induced mTORC1 activation may
be important for the growth of both normal and tumor cells.
21. PFKFB4 a novel autophagy regulator
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), promotes
pentose phosphate pathway and NADPH production critical for antioxidant
defense drives.
Loss of PFKFB4 promotes oxidative stress, triggering autophagy as a stress-
adaptive survival mechanism.
AM Strohecker , Oncogene (2015), 1 – 15
22. Future perspective
The identification of novel regulators of the lysosomal/mTORC1
pathway, and the interplay between nutrient sensing and disease.
Development of biomarkers is also needed to explain the differences
between an optimal dietary regime and starvation, taking into account
individual variation in genotype and epigenotype.
The identification of novel compounds that are able to modulate
lysosomal function, which could in turn be made into effective drugs to
promote cellular clearance.
Future strategies to manipulate lysosomal function might be of great
benefit for common diseases such as LSD diseases, cancer, and
neurodegenerative disorders.
23.
24. REFERENCES
1. C. Settembre, A. Ballabio Lysosome: regulator of lipid degradation pathways
Trends in Cell Biology, 24, 743 (2014).
2. C Settembre et al A lysosome-to-nucleus signalling mechanism senses and
regulates the lysosome via mTOR and TFEB The EMBO Journal VOL 31 |
NO 5 | 2012.
3. Luigi Fontana et. al. Promoting Health and Longevity through Diet:From
Model Organisms to Humans Cell 161, March 26, 2015.
4. C. Settembre, A. Fraldi, D. L. Medina, A. Ballabio, Signals from the
lysosome: a control centre for cellular clearance and energy metabolism Nat.
Rev.Mol. Cell Biol. 14, 283 (2013).
5. A. Folick et al., Lysosomal signaling molecules regulate longevity in
Caenorhabditis elegans Science 347, 83 (2015).
6. Daniel Ackerman, The mystery of C. elegans aging: An emerging role for fat
Bioessays 34: 466–471, 2012 WILEY Periodicals, Inc.
7. Robert T. Abraham, Making sense of amino acid sensing Science 347, 128
(2015).
25.
26. METABOLISM
You are not just what, but when you eat Limiting food intake to an 8-hour window that
corresponds to a time of high activity protects mice from obesity and metabolic disease
caused by a diet high in fat. Chaix et al. extended such studies to examine what would
happen in a regimen more adaptable to peoples’ lifestyles. Promisingly, they found
protective effects from fasting periods as short as 12 hours. Even better, mice showed
improved metabolic fitness even when they took the weekends off. This was most likely
because the changes in gene expression caused by restricting food during the week
continued even when mice had full access to food on the weekends.
Cell Metab. 20, 991 (2014).
Avoiding nighttime eating may reduce
the effects of an unhealthy diet
Hinweis der Redaktion
Dietary restriction (DR), the reduction of dietary intake without malnutrition. Results in many of the same physiological, metabolic, and molecular changes. Dietary Restriction Modulates Multiple Systemic, Neural, and Cellular Mechanisms that Improve Health and Combat the Diseases of Aging.Whether these regimens allpinpoint the same process is still unclear, and each one has its own merits and caveats. The molecular mechanisms responsible for the effects of
altered meal patterns on metabolic health are not fully understood.
There may be compensatory changes in energy sensing
pathways, such as AMPK, AKT/mTOR, and cyclic AMP
response element binding protein (CREB), which are all implicated
in cellular homeostasis and rhythmic oscillations of circadian
clock targetsaltered food intake, especially protein and insoluble
fiber, have rapid and profound effects on gut microbiota structure,
function, and secretion of factors that modulate multiple
inflammatory and metabolic pathways
Recently, some exciting progress has been made in identifying genes mediating DR
Several different mechanisms have been identified by which removal of the germline affects lipid metabolism in a manner that extends lifespan. First, loss of the germline causes a reduction in TOR expression, which induces lipase and autophagy expression via the two factors DAF-16 and PHA-4. In addition, germline loss also increases expression of the FAT-6 desaturase, which produces oleic acid from stearic acid. This suggests that germline loss induces a healthier lipid status, leading to increased longevity. How changes in lipid status affect longevity is unknown
our data offer a novel mechanism by which autophagy and the lipase LIPL-4 interdependently modulate aging in germline-deficient C. elegans by maintaining lipid homeostasis to prolong life span.
In response to depletion of the germ line, NHR-80 is up-regulated and becomes transcriptionally functional.
fat-6 is one of its targets and it encodes for a Stearoyl Co-A D9 Desaturase that produces OA. OA production is required, but not sufficient to promote
longevity in the absence of proliferating GSCs. Thus, the FAT-6/OA acts in concert with other NHR-80 critical targets (Crit. targets). The DAF-16/
K04A5.8 and the NHR-80 pathways can act independently, but DAF-12 is required for NHR-80 function. DAF-12 and NHR-80 do not interact at a
transcriptional level and we propose that DAF-12 and NHR-80 targets interact to promote longevity (fat-6 is not a DAF-12 target). The critical targets
could be shared by DAF-12 and NHR-80 or distinct. Alternatively, DAF-12 may physically interact directly with NHR-80 (grey
PKKKRKV nls
Lysosomes are involved in controlling the activity of mTOR and the execution of autophagy in
response to nutrient availability. LIPL-4 itself is important for inducing autophagy in C. elegans. Therefore, a key remaining question concerns the connection between this lysosome-to-nucleus signaling and the TOR-autophagy pathway. Could TOR and autophagy play a role in the longevity of LIPL-4–overexpressing animals
Consistent with this hypothesis, we found that TFEB interacts with mTOR on the lysosomal membrane and, through this interaction, it senses the lysosomal content This unique lysosome-to-nucleus signalling mechanism allows the lysosome to regulate its own function.
TFEB subcellular localization was analysed in HeLa and HEK-293Tcells transiently transfected with a TFEB–3FLAG plasmid and treated overnight with several inhibitors of lysosomal functionThese treatments included the use of chloroquine (CQ), an inhibitor of the lysosomal pH gradient, and Salicylihalamide A (SalA), a selective inhibitor of the v-ATPase as well as overexpression of PAT1, an amino acid transporter that causes massive transport of amino acids out of the lysosomal lumen
We postulated that TFEB uses the v-ATPase/mTORC1 sensing device on the lysosomal surface to modulate lysosomal function according to cellular needs
Unphosphorylated TFEB progressively accumulates in the nucleus, where it activates lysosomal gene expression programs aimed at correcting the defective nutrient and/or pH status of the lysosome
In particular, a molecular machinery that connects the presence of amino acids in the lysosomal lumen to the activation of mTORC1 indicates a new role for the lysosome in nutrient sensing and cellular growth control.
It also suggests that mTORC1 participates in a lysosomal adaptation mechanism that enables cells to cope with starvation and lysosomal stress conditions
A variety of potential metabolic controllers of autophagy and health span have already been proposed. However, precise strategies to target the correlating pathways (e.g., by nutrition patterns) remain to be elucidated in more detail. For example, it would be of great interest to determine if special diets that include the limitation of (defined) amino acids or the uptake of certain polyamines, like spermidine, influence the metabolism towards improved cellular conditions during agin Sirtuins are NADþ-dependent protein deacetylases. Sirtuins are stimulated by polyphenolics such as resveratrol.
This might bring up metabolomics as a future trend for aging analyses
AA is an essential nutrient and key chemical signal for cell growth and metabolism. mTORC1 controls cell growth in response to local amino acid availability and growth factor signaling. Over the last few years a lysosome-based amino acid sensing mechanism has been described by which amino acid sufficiency converts RagA/B to the GTP bound state and RagC/D to the GDP bound state, which recruits mTORC1 to the lysosomal surface, where its activator, the Rheb GTPase, resides (left). Thomas et al. (2014) now challenge the lysosome centric view of amino acid sensing by proposing an alternative mechanism in which amino acids activate the Rab1A GTPase, which then recruits mTORC1 to the surface of the Golgi (right). Whether these two mechanisms work in parallel as the authors propose or are part of contiguous endomembrane-based mTORC1 regulatory system remains to be seen.
In addition, a considerably more detailed understanding of the composition of lysosomal amino acid pools in nutrient-starved and -replete cells is needed to fully comprehend the regulation of mTORC1 by this organelle
Our recent findings showed that glutamine in combination with leucine activates mTOR pathway by enhancing glutaminolysis and αKG production
Many cancer cell lines have increased mTORC1 activity and show a high dependence on Gln for growth. Therefore, Gln-induced mTORC1 activation may be important for the growth of both normal and tumor cells. ext Graf 2.
Most of the currently used anticancer drugs are either nonselective for tumor cells or extend the lifespan of the patients only in terms of a few months to years. Obviously, new molecular targets are sorely needed to make progress in cancer treatment
Understanding physiological processes in biochemical and molecular details not only offers insight into disease pathogenesis, but also permits the development of new diagnostic and prognostic tools, as well as the design of novel therapeutic compounds. Lysosomes are key components of many cellular processes,which make them attractive therapeutic targets
These efforts will help us understand the complicated role of autophagy in cancer and facilitate the rational design of combinatorial strategies aimed at modulating autophagy
drug development activities in this space have focused on blocking mTORC1 activation, in part because hyperactivation of the pathway can lead to aberrant growth seen in cancer or metabolic abnormalities associated with diabetes
.
However, many exciting questions still await clarification, including how the whole cell adapts to starvation conditions,
conserved—mechanisms through which genetic and environmental intervention improve health during aging
Rapamycin, an mTOR inhibitor, is a clinically approved drug used as an immunosuppressive agent that reduces organ transplant rejection
