Page 8 - ITPS-8-2

INNOSC Theranostics and
Pharmacological Sciences AMPK in metabolism, energy and aging

In 1987, researchers David Carling and Grahame promoting mitochondrial gene expression and increasing
Hardie hypothesized the existence of two protein mitochondria numbers. One of these regulators of multiple
kinases that inhibited enzymes involved in the de novo mitochondrial genes is peroxisome proliferator-activated
synthesis of fatty acids (acetyl-CoA carboxylase [ACC]) receptor-γ coactivator-1α (PGC-1α), which, in muscle,
and cholesterol (hydroxymethylglutaryl-CoA reductase promotes the conversion of type IIb muscle fibers to
[HMG-CoA reductase]). Subsequent studies revealed that type I and type IIa fibers, both characterized by increased
both kinases were, in fact, the same protein. Studies on mitochondrial content. 15,16
1,2
experimental animals have presented data confirming The γ subunit of AMPK contains two Bateman domains,
that physical exercise decreases the muscle concentration which serve as binding sites for adenosine monophosphate
of malonyl-CoA formed during the ACC pathway, (AMP) and ATP. Therefore, when the cell does not detect an
which contributes to more efficient utilization of energy energy deficiency, ATP molecules bind to the appropriate
substrates. Under normal physiological conditions, site on the enzyme, maintaining it in an inactive state.
3
malonyl-CoA inhibits carnitine palmitoyltransferase I, Conversely, if the AMP/ATP ratio exceeds unity, AMP
blocking the transport of fatty acids into the mitochondria molecules bind to the Bateman subunit, triggering the
where they would otherwise be oxidized. Consequently, activation of the enzyme through three mechanisms:
a decrease in malonyl-CoA concentration promotes fatty • Allosteric activation;
acid transport into mitochondria, facilitating their use for • Stimulation of AMPK activating proteins, which
ATP production. 4
phosphorylate the α catalytic subunit;
AMPK is a metabolic sensor responsible for • Preventing dephosphorylation as a result of
maintaining homeostasis, metabolic control, and energy AMP binding to the γ subunit which extends the
balance by monitoring energy status and matching energy phosphorylation of the α subunit.
production to its consumption. Following favorable
metabolic outcomes after AMPK activation, it has been The primary protein kinases that activate AMPK are
identified as an important therapeutic target. Its activation liver kinase B1 (LKB1) and calcium-calmodulin-dependent
5
17,18
is triggered when low energy levels are detected, indicated protein kinase α and β (CaMKK). In response to
by reduced adenosine triphosphate (ATP) levels, which energy-related stress, such as an energy deficit or depletion,
can occur during fasting, hypoxia, or when various toxic skeletal muscle shows increased LKB1 activity. Conversely,
substances impact the electron transport chain (ETC) and the absence of this protein is associated with reduced
inhibit oxidative phosphorylation (OXPHOS). 6,7 physical endurance. CaMKK exists in two isoforms, α and
β, which are 70% similar. These isoforms become active
AMPK exists as a heterotrimeric complex, consisting in the presence of Ca and calmodulin and are capable
2+
of a catalytic α subunit (α , α ) encoded by PRKAA1; of phosphorylating AMPK in the brain, endothelium,
1
2
regulatory β subunits (β , β ) encoded by PRKAB1 and lymphocytes, and striated muscles. Given that the enzyme
1
2
PRKAB2; and γ subunit (γ , γ , γ ) encoded by PRKAG1, has multiple subunits with multiple isoforms, it can be
1
3
2
PRKAG2, and PRKAG3. These subunits are encoded in the inferred that AMPK also exists in multiple forms, as shown
genomes of all cells, suggesting that the AMPK heterotrimer in Table 1. Among them, the α β γ isoform is activated
2 2 3
arose very early in the evolution of eukaryotic cells. One under conditions of short-term physical exercise, while the
8,9
of the most important event in this evolution was the α β γ isoform is present in long-term effort. 2
endosymbiotic capture of aerobic bacteria, which gave 2 2 1
rise to mitochondria. After this event, the newly formed 2. AMPK activators and physical activity
organism developed new abilities to convert adenosine For most compounds that activate AMPK, the activation
diphosphate (ADP) into ATP and established signaling occurs by inhibiting the ETC, leading to an increase in ADP
pathways to monitor ATP availability. In evolved organisms, and/or AMP levels. Another important aspect to consider
AMPK’s role in ATP regulation, mitochondrial biogenesis, is the functional differences between AMPK isoforms.
mitophagy, and fission underscores its significance as a link
between mitochondria (aerobic bacteria) and the host cell A study of transgenic mice deficient in AMPKα
2
(anaerobic bacteria). 10-13 While AMPK initially served a showed that in the absence of this enzyme, the contractility
primordial role in energy regulation, it has evolved to also of the heart is impaired, indicating that the absence of the
regulate the energy balance of the whole organism through α isoform is correlated with reduced physical capacity.
2
hormone-mediated responses in the hypothalamus. In contrast, mice injected with 5-Aminoimidazole-4-
3,14
The adaptability of the eukaryotic cell ensures cellular carboxamide ribonucleoside (AICAR, a known AMPK
homeostasis and survival under adverse conditions. In modulator) showed improved running capacity, enhanced
athletes, AMPK activation may confer advantages by endurance, increased oxygen consumption, and decreased
Volume 8 Issue 2 (2025) 2 doi: 10.36922/itps.4852