Adaptation to Energy Depletion—The

Adaptation to Energy Depletion—The Energy Stress Response
Cells try to maintain their adenosine nucleotide pool in triphosphorylated,
energized state, which is in the form of ATP. When the
re-phosphorylation rate of AMP and ADP to ATP does not keep
up with the rate of ATP use, because, for example, oxidative phosphorylation
is impaired or ATP use for muscle contraction or ion
pumping is excessive, the ratio of AMP to ATP increases. A cellular
mechanism has evolved to sense this menacing energy deficit
and, in order to compensate, boosts ATP production and curtails
ATP consumption (Hardie et al., 2006). The sensor is a ubiquitous
heterotrimeric intracellular protein complex called AMP-activated
protein kinase (AMPK). AMP strongly activates AMPK allosterically,
and also by making it susceptible for phosphorylation by protein
kinase LKB1 (or by the calmodulin dependent protein kinase
kinase, CaMKK, in neurons). The phosphorylated, and thus activated
AMPK, targets two sets of proteins. One set includes those
whose activation facilitates ATP production from catabolism of glucose
and fatty acids as well as by promoting the biogenesis of mitochondria.
For example, AMPK activation increases (a) glucose
uptake (via recruiting to the cell membrane or activating glucose
transporters GLUT4 and GLUT1), (b) glycolysis (via phosphorylation
and activation of 6-phosphofructo-2-kinase (PFK-2) whose
product, fructose-2,6-bisphosphate is a glycolytic activator), and (c)
fatty acid oxidation in mitochondria (via phosphorylation and inactivation
of acetyl-CoA-carboxylase, whose product, malonyl-CoA, is
an allosteric inhibitor of carnitine palmitoyltransferase-1, or CPT-1,
which mediates uptake of long-chain fatty acid CoA esters into
mitochondria). Another set of proteins, which are inactivated by
AMPK (directly or indirectly), include those that are involved in
biosynthetic ATP consuming reactions. Thus, AMPK inhibits (a)
glycogen synthesis via phosphorylation and inactivation of glycogen
synthase, (b) lipid synthesis by phosphorylating and inactivating
acetyl-CoA-carboxylase, whose product, malonyl-CoA, is an
essential substrate for fatty acid synthesis, (c) cholesterol synthesis
by phosphorylating and inactivating HMG-CoA reductase, (d)
glucose synthesis via inactivating phosphorylation of a transcriptional
coactivator, TORC2, which then decreases expression of key
gluconeogenetic enzymes, such as phosphoenolpyruvate carboxykinase
(PEPCK) and glucose-6-phosphatase, and (e) protein synthesis,
and thus cell growth, by inhibiting the protein kinase mTOR
(Fig. 3-25). AMPK-mediated modulation of cellular energy supply
and consumption involves mainly kinase reactions rather than new
protein synthesis. Therefore, this adaptation is a rapid process. It can
be a response to any harmful condition that compromises oxidative
phosphorylation, such as hypoxia, hypoglycemia (especially in neurons)
and chemically induced mitochondrial toxicity. For example,
cells exposed to arsenite exhibit rapid increases in the AMP/ATP
ratio and AMPK activity, with concomitant declines in HMG-CoA
reductase activity as well as fatty acid and cholesterol synthesis
(Corton et al., 1994).
After surveying the major cellular adaptation mechanisms to
toxicants, it is easy to recognize that one noxa may initiate several
adaptive responses. For example, cells exposed to a hypoxic environment
can rapidly respond with both AMPK-mediated program
of energy stabilization, and HIF-1α-directed adaptation to oxygen
shortage. Theoretically, an electrophile toxicant that can bind covalently
to cellular macromolecules and can also generate oxidative
stress, such as a redox cycling quinone, would be expected to induce
a number of adaptive processes, including the electrophile response,
the heat-shock response, the endoplasmic-reticulum stress response,
the DNA-damage response, and the proliferative response, and if it

Results (Indonesian) 1:

Adaptation to Energy Depletion—The Energy Stress ResponseCells try to maintain their adenosine nucleotide pool in triphosphorylated,energized state, which is in the form of ATP. When there-phosphorylation rate of AMP and ADP to ATP does not keepup with the rate of ATP use, because, for example, oxidative phosphorylationis impaired or ATP use for muscle contraction or ionpumping is excessive, the ratio of AMP to ATP increases. A cellularmechanism has evolved to sense this menacing energy deficitand, in order to compensate, boosts ATP production and curtailsATP consumption (Hardie et al., 2006). The sensor is a ubiquitousheterotrimeric intracellular protein complex called AMP-activatedprotein kinase (AMPK). AMP strongly activates AMPK allosterically,and also by making it susceptible for phosphorylation by proteinkinase LKB1 (or by the calmodulin dependent protein kinasekinase, CaMKK, in neurons). The phosphorylated, and thus activatedAMPK, targets two sets of proteins. One set includes thosewhose activation facilitates ATP production from catabolism of glucoseand fatty acids as well as by promoting the biogenesis of mitochondria.For example, AMPK activation increases (a) glucoseuptake (via recruiting to the cell membrane or activating glucosetransporters GLUT4 and GLUT1), (b) glycolysis (via phosphorylationand activation of 6-phosphofructo-2-kinase (PFK-2) whoseproduct, fructose-2,6-bisphosphate is a glycolytic activator), and (c)fatty acid oxidation in mitochondria (via phosphorylation and inactivationof acetyl-CoA-carboxylase, whose product, malonyl-CoA, isan allosteric inhibitor of carnitine palmitoyltransferase-1, or CPT-1,which mediates uptake of long-chain fatty acid CoA esters intomitochondria). Another set of proteins, which are inactivated byAMPK (directly or indirectly), include those that are involved inbiosynthetic ATP consuming reactions. Thus, AMPK inhibits (a)glycogen synthesis via phosphorylation and inactivation of glycogensynthase, (b) lipid synthesis by phosphorylating and inactivatingacetyl-CoA-carboxylase, whose product, malonyl-CoA, is anessential substrate for fatty acid synthesis, (c) cholesterol synthesisby phosphorylating and inactivating HMG-CoA reductase, (d)glucose synthesis via inactivating phosphorylation of a transcriptionalcoactivator, TORC2, which then decreases expression of keygluconeogenetic enzymes, such as phosphoenolpyruvate carboxykinase(PEPCK) and glucose-6-phosphatase, and (e) protein synthesis,and thus cell growth, by inhibiting the protein kinase mTOR(Fig. 3-25). AMPK-mediated modulation of cellular energy supplyand consumption involves mainly kinase reactions rather than newprotein synthesis. Therefore, this adaptation is a rapid process. It canbe a response to any harmful condition that compromises oxidativephosphorylation, such as hypoxia, hypoglycemia (especially in neurons)dan toksisitas mitokondria induksi pembungan secara kimia. Sebagai contoh,sel-sel yang terkena arsenite menunjukkan kenaikan cepat AMP/ATPrasio dan aktivitas AMPK, dengan penurunan seiring HMG-CoAaktivitas reduktase serta lemak asam dan kolesterol sintesis(Corton et al., 1994).Setelah mengamati mekanisme utama selular adaptasi untuktoxicants, sangat mudah untuk mengenali noxa bahwa satu mungkin memulai beberaparespons adaptif. Sebagai contoh, sel-sel yang terkena lingkungan hipoksiadapat cepat merespon dengan kedua program AMPK-dimediasi.energi stabilisasi, dan adaptasi HIF-1α-diarahkan untuk oksigenkekurangan. Secara teoritis, toxicant electrophile yang dapat mengikat berikatan kovalen denganuntuk seluler makromolekul dan juga dapat menghasilkan oksidatifstres redoks Bersepeda quinone, diharapkan untuk menginduksisejumlah proses adaptif, termasuk electrophile respon,panas-shock respon, respon stres endoplasmic-sarkoplasma,respon kerusakan DNA, dan respon proliferatif, dan jika itu