As scientific research advances, increasing evidence suggests that AMP-activated protein kinase (AMPK) plays a crucial role in maintaining cellular energy balance and regulating mitochondrial processes. AMPK, a protein kinase capable of sensing cellular energy status, specifically regulates the synthesis, fission, and autophagy of mitochondria to maintain the healthy state of the cellular mitochondrial network.
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Fig. 1 Regulation of mitochondrial homeostasis by AMPK (Herzig S., Shaw R. J. 2018).
AMPK's Regulation of Mitochondrial Synthesis
Mitochondria, the cellular powerhouses responsible for ATP production, undergo synthesis to increase energy output, involving processes such as mitochondrial growth, fission, and the generation of new mitochondria. The synthesis of mitochondria requires the upregulation of mitochondrial protein expression, increased lipid production and transport to maintain the enlargement of the mitochondrial membrane surfaces. Mitochondrial genes and nuclear genes jointly encode mitochondrial proteins, with most mitochondrial proteins encoded by nuclear genes. Therefore, signals stimulating mitochondrial synthesis need to be transmitted to the cell nucleus, activating transcription factors to induce the synthesis of mitochondrial proteins.
Exercise has long been established as a condition that enhances mitochondrial synthesis. As early as the 1950s, researchers observed a higher mitochondrial content in active muscles, indicating a correlation between muscle activity and mitochondrial quantity. Today, it is well-established that exercise and physical activity induce mitochondrial synthesis, enhancing muscle oxidative capacity. Interestingly, exercise is also an effective activator of AMPK, further confirming the crucial role of AMPK in the process of mitochondrial synthesis. Prolonged activation of AMPK has been shown to increase mitochondrial synthesis, and the AMPK activator AICAR mimics the effects of exercise. Experimental evidence demonstrates that AMPK plays a critical regulatory role in mitochondrial biosynthesis.
AMPK's control over mitochondrial quantity and quality extends beyond muscle cells to various tissues, such as adipocytes, macrophages, and hepatocytes. It governs both the number and quality of mitochondria, impacting cellular energy metabolism and overall physiological well-being. Downstream effectors of AMPK, including proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), estrogen-related receptors (ERRs), and peroxisome proliferator-activated receptor gamma (PPARγ), actively participate in the orchestration of mitochondrial synthesis by AMPK. Through the regulation of gene transcription and expression, these effectors influence the synthesis and functionality of mitochondrial proteins, thereby preserving the stability of the mitochondrial network.
AMPK in Mitochondrial Autophagy
Autophagy is a prevalent intracellular self-degradation mechanism responsible for eliminating impaired proteins, organelles, and cellular fragments to uphold cellular equilibrium. AMPK, serving as a protein kinase with the ability to perceive cellular energy levels, assumes a pivotal regulatory role in orchestrating the autophagic process. AMPK exerts direct or indirect control over essential proteins across various autophagic pathways, including the phosphorylation of Unc-51-like autophagy-activating kinase 1 (ULK1). This regulatory cascade encompasses diverse molecular pathways, such as the AMPK-mTOR pathway and the AMPK-Ulk1 pathway.
AMPK plays a crucial role in the mitochondrial autophagy process. The activation of AMPK initiates mitochondrial autophagy, leading to the clearance of damaged mitochondria and the preservation of overall mitochondrial health. Mitochondrial autophagy plays a dual role by assisting cells in producing extra ATP during energy shortages and protecting cells from oxidative damage by removing dysfunctional mitochondria. Therefore, the crucial involvement of AMPK in the regulation of mitochondrial autophagy emphasizes its significance in maintaining cellular energy equilibrium and promoting adaptation to environmental fluctuations.
AMPK in Extracellular Mitophagy
Autophagy goes beyond intracellular functions to engage in interactions with other cells or extracellular components, a phenomenon referred to as heterophagy. This variant of autophagy encompasses various roles such as defending against pathogens, eliminating extracellular bacteria, and modulating immune responses. AMPK, in this context, also plays a pivotal role in exerting regulatory control.
The activation of AMPK serves to enhance cellular defense mechanisms against pathogen clearance. By modulating the autophagic process, AMPK aids in eliminating infected cells and pathogens, thereby preserving the immune system's homeostasis. The regulatory framework of heterophagy entails the involvement of multiple signaling pathways, with AMPK serving as a crucial regulatory factor in this intricate process.
Transcriptional Regulation of Autophagy by AMPK
The autophagic process involves not only the phosphorylation and degradation of proteins but also the transcriptional regulation of genes associated with autophagy. Within this intricate mechanism, AMPK selectively regulates the expression of autophagy-related genes by directly phosphorylating FOXO family transcription factors and indirectly influencing factors such as transcription factor EB (TFEB).
AMPK directly impacts the expression of autophagy-related genes by phosphorylating FOXO family transcription factors. These transcription factors, essential for autophagy regulation, undergo activity modulation through phosphorylation. The activation of AMPK inhibits FOXO activity by phosphorylation, consequently influencing the transcription of genes associated with autophagy.
In summary, AMPK, a protein kinase adept at detecting cellular energy levels, serves a crucial regulatory function in preserving cellular energy equilibrium and adjusting to diverse environmental circumstances. Extending its influence from mitochondrial synthesis to the control of mitochondrial dynamics and the modulation of autophagic mechanisms, AMPK participates in regulating numerous cellular processes through diverse pathways, constructing an extensive regulatory network. A more profound comprehension of the interplay between AMPK and mitochondria has the potential to offer fresh perspectives for the development of therapeutic strategies in associated diseases.
References
- Herzig S.; Shaw R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nature Reviews Molecular Cell Biology. 2018, 19(2): 121-135.
- Li Y.; Chen Y. AMPK and autophagy. Autophagy: Biology and Diseases: Basic Science. 2019: 85-108.
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