Energy metabolism in health and diseases

Abstract

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Fig. 1

Diagram of energy metabolism alterations, detection, and therapeutics. a Energy metabolic alterations accompany a variety of diseases, which include increased energy demands and shifts in energy production pathways, ultimately leading to mitochondrial dysfunction-based metabolic disorders that cause functional abnormalities or cell death in normal cells. b Detection methods for altered energy metabolism encompass established spectroscopic assays, as well as advanced imaging techniques such as MRI and PET/CT, and the burgeoning field of metabolomics, including spatial omics technologies. c Pharmacological interventions targeting changes in energy metabolism are directed at multiple stages of metabolic pathways, including glycolysis, fatty acid oxidation and mitochondrial oxidation, to ameliorate abnormal energy metabolic shifts

Fig. 2

The milestones of energy metabolism development. The field of energy metabolism research originated in the mid-19th century and experienced rapid growth throughout the 20th century. Historical milestones, including the establishment of the law of energy conservation, the discovery of the Warburg effect, the identification of ATP, and the elucidation of the TCA cycle, have significantly advanced our understanding of energy metabolic processes and led to the revelation of multiple metabolic pathways. With the advent of the 21st century, researchers are extensively investigating the regulatory mechanisms of energy metabolism and actively exploring methods for its detection, as well as therapeutic strategies targeting energy metabolism for disease treatment

Fig. 3

Main pathways for cellular energy production and molecular signal regulation. Glycolysis begins with the phosphorylation of glucose by hexokinase (HK), producing 6-phosphogluconate. Subsequently, phosphofructokinase-1 (PFK-1) converts 6-phosphofructose into 1,3-bisphosphoglycerate. In the subsequent cleavage reaction, aldolase (ALDO) cleaves 1,3-bisphosphoglycerate into two molecules of 3-phosphoglyceraldehyde. 3-phosphoglyceraldehyde is oxidized to 1,3-bisphosphoglycerate under the catalysis of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and reduced coenzyme II (NADH) is produced in the process. Thereafter, 1,3-bisphosphoglycerate is converted into 3-phosphoglycerate by phosphoglycerate kinase (PGK1), generating one molecule of ATP. 3-phosphoglycerate is then transformed into 2-phosphoglycerate by phosphoglycerate mutase (PGAM1), and then catalyzed by enolase (ENO1) to form 2-phosphoenolpyruvate. 2-phosphoenolpyruvate is ultimately converted into pyruvate under the action of pyruvate kinase (PK), releasing another molecule of ATP. Under anaerobic conditions, pyruvate is reduced to lactate by lactate dehydrogenase (LDH). Fatty acids first need to be activated into acyl-CoA (acyl-coenzyme A). After activation, the fatty acids are transferred from the cytoplasm to the mitochondrial matrix through Carnitine palmitoyltransferase I (CPT1). The fatty acids undergo a series of β-oxidation cycles, resulting in the production of acetyl-CoA and NADH. Glutamine enters the cell through ASCT2/SLC1A5 and is converted into glutamate by the deamination reaction catalyzed by glutaminase (GLS). Glutamate can be further converted into alpha-ketoglutarate (α-KG). Nutrient-derived acetyl-CoA enters the TCA cycle, which is catalyzed by enzymes such as succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), ultimately producing energy molecules ATP and reducing agents NADH and FADH2. NADH and FADH2 enter OXPHOS to further generate ATP. In the aforementioned process, various signaling molecules, such as AMP-activated protein kinase (AMPK), phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), mechanistic target of rapamycin complex (mTORC), and sirtuins (SIRT), play crucial regulatory roles in controlling energy production under physiological conditions. PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; GDH, glutamate dehydrogenase; ACS, acyl-CoA synthetase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; ACLY, ATP citrate lyase

Fig. 4

Energy metabolism in ischemic heart disease and ischemia-reperfusion injury. Under physiological conditions, the heart primarily relies on the oxidation of fatty acids entering the TCA cycle for energy supply. In various disease states (a ischemic heart disease and b ischemia-reperfusion injury), changes in cardiac energy metabolism led to increased production of ROS, ultimately affecting mitochondrial function and resulting in decreased ATP production, which impacts the heart’s ability to perform its functions. FAO fatty acid oxidation, PFK phosphofructokinase, BCAA branched-chain amino acids, HK hexokinase, PK pyruvate kinase, ACS acyl-CoA synthetase

Fig. 5

Energy metabolism in heart failure and diabetic heart disease. Under physiological conditions, the heart primarily relies on the oxidation of fatty acids entering the TCA cycle for energy supply. In various disease states (a heart failure and b diabetic heart disease), changes in cardiac energy metabolism led to increased production of ROS, ultimately affecting mitochondrial function and resulting in decreased ATP production, which impacts the heart’s ability to perform its functions. FAO fatty acid oxidation, PFK phosphofructokinase, BCAA branched-chain amino acids, HK hexokinase, PK pyruvate kinase, ACS acyl-CoA synthetase

Fig. 6

Energy metabolism in autoimmune diseases. In autoimmune diseases, metabolic abnormalities in immune cells are a key factor. In some situations, CD4⁺ T cells enhance glycolysis and mitochondrial OXPHOS, while in rheumatoid arthritis (RA), T cells suffer from impaired mitochondrial OXPHOS, turning to the pentose phosphate pathway. Naive Th cells and B cells tend to undergo aerobic oxidation, while activated Th cells and B cells tend to undergo glycolysis. Treg cells can utilize glycolysis and lactate to maintain their functions in the TME. M1 macrophages tend to have aerobic glycolysis, while M2 macrophages rely more on OXPHOS. FLSs undergo metabolic reprogramming, shifting towards enhanced glycolysis. As antigen-presenting cells, DCs significantly alter their metabolic pathways, such as OXPHOS and glycolysis, during activation. These changes in energy metabolism promote the abnormal proliferation of fibers and blood vessels and exacerbate the inflammatory process. DC dendritic cells, FLS fibroblast-like synoviocytes, Treg regulatory T cells, MDSC myeloid-derived suppressor cells

Fig. 7

Energy metabolism in cancer. Cancer cells undergo metabolic reprogramming in their energy metabolism, characterized by enhanced glycolysis, glutamine metabolism, and FAO, but the TCA cycle and OXPHOS are suppressed. The activity of glycolysis-related transport proteins and enzymes such as GLUT, HK, PFK, PK, and LDH is increased. The activity of glutamine transporters and GLS is increased, catalyzing the production of glutamate for biosynthesis or energy synthesis. The expression of fatty acid transport proteins (CD36) and synthetic proteins (ACLY, ACC, FASN) is increased. However, the activity of key enzymes in the TCA cycle, such as IDH, SDH, FH, and MDH, is suppressed. A variety of signaling molecules undergo changes in expression during this process and regulate the energy metabolism of cancer cells. Overall, HIF1-α, KRAS, SALL4, c-MYC, PI3K/AKT, and mTOR, among others, play pro-oncogenic roles mainly by promoting glycolysis and glutaminolysis while inhibiting the TCA cycle and oxidative phosphorylation. P53, PTEN, AMPK, NRF2, PCG1α, and others play tumor-suppressive roles, inhibiting glycolysis and fatty acid transport and synthesis while promoting the mitochondrial TCA cycle and oxidative phosphorylation processes (red boxes: promoting signaling molecules; blue boxes: inhibitory signaling molecules). HK hexokinase, PFK phosphofructokinase, PK pyruvate kinase, ALDHO aldehyde dehydrogenase, GAPDH glyceraldehyde-3-phosphate dehydrogenase, PGK1 phosphoglycerate kinase 1, LDH lactate dehydrogenase, PDH pyruvate dehydrogenase, PDK1 pyruvate dehydrogenase kinase 1, ACLY ATP citrate lyase, ACC acetyl-CoA carboxylase, FASN fatty acid synthase, ACS acetyl-CoA synthase, GLS glutaminase, GDH glutamate dehydrogenase, IDH isocitrate dehydrogenase, SDH succinate dehydrogenase, FH fumarate hydratase, MDH malate dehydrogenase, CPT1 carnitine palmitoyltransferase 1

Fig. 8

Energy metabolism-driven alterations in the TME. a The enhancement of the Warburg effect in cancer cells leads to glucose scarcity in the microenvironment, triggering competition for glucose between immune and cancer cells, which suppresses energy production in immune cells. Increased glycolysis results in the accumulation of lactate and a decrease in pH within the microenvironment. Lactic acid and low pH inhibit the function of M1 macrophages, activated T cells, and NK cells, reducing the secretion of inflammatory cytokines, perforin, and granzymes, thereby diminishing their cytotoxic capabilities. However, lactate promotes the growth of M2 macrophages, MDSCs, Tregs, and CAFs, potentially due to increased expression of glucose transporters and MCT-1, thus facilitating adaptation to the microenvironment. b Metabolic shifts in mitochondrial OXPHOS lead to the accumulation of intermediates such as acetyl-CoA, succinate, and fumarate. These intermediates promote epithelial-mesenchymal transition (EMT) in cancer cells and further recruit suppressive cells like MDSCs and Tregs through the release of TGF-β and IL-8. c Enhanced FAO promotes the expression of CD36, which facilitates energy production in Tregs, M2 macrophages, and cancer cells but exerts an inhibitory effect on activated T cells and DCs. d Increased glutaminolysis leads to glutamine depletion, thereby inhibiting the function of activated T cells and NK cells, reducing the release of pro-inflammatory cytokines such as TNF-α and IFN-γ, and promoting immune evasion. HK hexokinase, PFK phosphofructokinase, LDH lactate dehydrogenase, DC dendritic cells, Treg regulatory T cells, MDSC myeloid-derived suppressor cells, GSH glutathione

Fig. 9

Methods for detecting energy metabolism. MRI magnetic resonance imaging, PET positron emission tomography, HPLC high-performance liquid chromatography, GC gas chromatography, MS mass spectrometry, CE-MS capillary electrophoresis-mass spectrometry

Fig. 10

Targeting energy metabolism for cancer and neurodegenerative disease therapy. In cancer, owing to the significant increase in glycolysis, therapeutic drugs are often used to target the glycolytic process. In neurodegenerative diseases, because of mitochondrial dysfunction, therapeutic drugs are often used to target the mitochondrial metabolic process

Fig. 11

Targeting energy metabolism for cardiovascular disease therapy. a Various drugs, by targeting the expression of glucose transport proteins and glycolytic enzymes, can increase energy production in the heart and inhibit the process of oxidative stress. b Medications that target FAO inhibit the highly oxygen-consuming process of FAO and synthesis, shifting towards glycolysis, which can maintain the stability of heart function under hypoxic conditions. c By targeting mitochondria to maintain the stability of the TCA cycle and the electron respiratory chain, the generation of ROS can be reduced, ATP production can be promoted, and the stability of the heart can be maintained. d By supplementing with external energy substances, including ketone bodies and branched-chain amino acids, the energy synthesis and functional stability of the heart can be promoted