AMPK: keeping the (power)house in order?

Abstract

Metabolically energetic organs, such as the brain, require a reliable source of ATP, the majority of which is provided by oxidative phosphorylation in the mitochondrial matrix. Maintaining mitochondrial integrity is therefore of paramount importance in highly specialized cells such as neurons. Beyond acting as cellular 'power stations' and initiators of apoptosis, neuronal mitochondria are highly mobile, transported to pre-and post-synaptic sites for rapid, localized ATP production, serve to buffer physiological and pathological calcium and contribute to dendritic arborization. Given such roles, it is perhaps unsurprising that recent studies implicate AMP-activated protein kinase (AMPK), a cellular energy-sensitive metabolic regulator, in triggering mitochondrial fission, potentially balancing mitochondrial dynamics, biogenesis and mitophagy.Although the brain constitutes approximately only 2% of our total body weight, it accounts for the usage of in excess of 20% of our oxygen intake and is one of the most metabolically active tissues in our bodies. Approximately 90% ATP production occurs through oxidative phosphorylation in mitochondria, therefore, for tissues with a high metabolic rate such as the brain, regulating mitochondrial health is key to sustaining cellular function [1].Mitochondria are dynamic, double-membraned organelles that continually undergo fission, fusion and quality control (mitophagy) [2]. Long-term failure of either fission or fusion can lead to deleterious consequences and thus, a balance of these processes together with mitophagy is critical to maintaining cellular homoeostasis. Over the last 20 years, there has been a flurry of interest in discerning the molecular mechanisms regulating this mitochondrial life cycle, with significant success. Inner and outer mitochondrial membrane fusion are governed by optic atrophy (OPA)1 and mitofusin1/2 respectively whereas fission is mediated by the cytosolic protein, dynamin-related protein (Drp)1 (Figure 1) [3]. Drp1 is recruited to the mitochondrial outer membrane by binding to one of a number of mitochondrially located adaptors such as mitochondrial fission factor (Mff) and mitochondrial fission protein (Fis)1, mitochondrial dynamics proteins of 49 and 51 kDa (MiD49/51) [2,4]. Mitophagy plays a key role in the life cycle of the mitochondrion. Not only does it ensure that damaged mitochondria are neutralized, but physiological mitophagy can also regulate the number of mitochondria and their turnover [5]. In response to the decorating of the outer membrane of a depolarized mitochondrion with ubiquitin, an isolation membrane is recruited to extend round and engulf the mitochondrion, subsequently fusing with a lysosome to acidify and recycle the contents (Figure 1). Fission is frequently observed as a prelude to mitophagy as well as in the initiation of apoptosis [6]. Fusion generates a mitochondrial reticulum, allowing mitochondrial contents to mix, preventing the accumulation of mitochondrial DNA mutations as well as promoting enhanced ATP synthesi...

Chinese olive ( Canarium album L.) fruit regulates glucose utilization by activating AMP‐activated protein kinase

“…When activated, AMPK phosphorylates mitochondrial fission factor (MFF), recruiting Drp1 from the cytosol to the mitochondrial outer membrane, thus promoting the constriction and fission of mitochondria, which may serve as one way for engulfment of mitochondria by autophagosome or mitophagy because of mitochondrial fragments that indicate extensive damage 56 . In our study, we found that CO‐EtOAc led to increased protein expression of DRP1 in mitochondrial and AMPK activation was essential for their full action in the promotion of mitochondrial fission, which has been reported to be a consequence of ATP depletion 57 …”

“…56 In our study, we found that CO-EtOAc led to increased protein expression of DRP1 in mitochondrial and AMPK activation was essential for their full action in the promotion of mitochondrial fission, which has been reported to be a consequence of ATP depletion. 57 In conclusion, our studies demonstrated the beneficial effects of a natural product, CO-EtOAc, as a potent activator of AMPK, which regulates glucose homeostasis both in vitro and in vivo. CO-EtOAc caused inhibition of mitochondrial oxygen consumption, thus leading to the activation of AMPK and subsequent beneficial metabolic outcomes, including enhanced glucose uptake and glycogen content in skeletal muscle cells (Figure 9).…”

Puerarin Attenuates Oxidative Stress and Ferroptosis via AMPK/PGC1α/Nrf2 Pathway after Subarachnoid Hemorrhage in Rats

“…As modulators of intracellular energy status, both AMPK and PGC1α are extremely active after brain injury [ 47 ]. Gao et al [ 48 ] found that AMPK/PGC1α pathway activation protected mitochondrial biosynthesis and function in cerebral ischemic stroke, while inhibition of this pathway can aggravate cerebral ischemia/reperfusion injury [ 49 ].…”

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

“…Stress-associated AMPK activation occurs from a direct mechanism involving depleted adenosine triphosphate (ATP) levels that raise cytoplasmic adenosine mono/diphosphate (AMP/ADP) levels [ 109 , 110 ] ( Figure 4 ). AMPK is also activated by three upstream regulators in response to different stimuli: (1) liver kinase B1 (LKB1), which responds to cellular energy levels; (2) Ca 2+ /calmodulin-dependent kinase kinase β (CaMKKß) activation by increased cytoplasmic calcium (Ca 2+ ) from ER stress; and (3) transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) [ 106 , 107 , 111 , 112 ] [ 113 , 114 ] ( Figure 4 ).…”

“…Once activated, AMPK upregulates autophagy via from 3 major pathways: (1) phosphorylation and deactivation of Raptor (a protein within the mTORC1); (2) activation of TSC2, causing RHEB inhibition and subsequent mTORC1 inhibition; and (3) ULK1 phosphorylation at Ser317 and Ser777 sites [ 53 , 54 , 94 , 115 ] ( Figure 4 ). It should also be noted that the activation of TSC2 can directly oppose the PI3K pathway-induced autophagic suppression [ 106 , 107 , 111 ]. Collectively, AMPK is a vital autophagic activator which has a complex, yet well understood, mechanism of activating autophagy.…”