Metabolism and Bioenergetics: Energy in Living Systems

Introduction to Metabolism

Metabolism encompasses all chemical reactions in living cells, divided into catabolic reactions (breaking down molecules to release energy) and anabolic reactions (building complex molecules using energy). ATP (adenosine triphosphate) is the universal energy currency linking catabolic and anabolic pathways—its hydrolysis drives endergonic reactions throughout the cell. Bioenergetics studies how free energy from oxidation of organic molecules is captured in ATP and used to perform biological work including biosynthesis, membrane transport, movement, and signalling.

Understanding metabolism is clinically essential: metabolic syndrome (obesity, insulin resistance, type 2 diabetes, dyslipidaemia) is the world's most prevalent non-communicable disease cluster; inborn errors of metabolism cause severe childhood diseases; cancer extensively reprograms metabolism; and mitochondrial diseases affect 1 in 5000 individuals. Most drugs act on metabolic enzymes, transporters, or their regulators. The metabolome—the complete set of small-molecule metabolites—reflects physiological and pathological states, enabling metabolomic biomarker discovery.

Central Metabolic Pathways

Glycolysis and Gluconeogenesis

Glycolysis converts glucose to pyruvate in the cytoplasm, yielding 2 ATP and 2 NADH per glucose. Key regulated enzymes—hexokinase, phosphofructokinase-1, pyruvate kinase—are inhibited by their products (feedback regulation). In anaerobic conditions, pyruvate is converted to lactate regenerating NAD+ to sustain glycolysis. Gluconeogenesis runs reverse glycolysis in the liver and kidneys using oxaloacetate as starting material, providing glucose during fasting, bypassing the irreversible glycolytic steps with distinct enzymes (PEPCK, FBPase-1, glucose-6-phosphatase). Metformin inhibits gluconeogenesis by activating AMPK, its primary mechanism for lowering blood glucose in type 2 diabetes.

Citric Acid Cycle and Oxidative Phosphorylation

Pyruvate enters mitochondria where pyruvate dehydrogenase generates acetyl-CoA, which condenses with oxaloacetate entering the citric acid cycle (TCA/Krebs cycle). Eight enzymatic steps fully oxidise acetyl groups to CO2, generating NADH and FADH2. Electrons from NADH and FADH2 flow through the mitochondrial electron transport chain (complexes I-IV) to O2, pumping protons across the inner membrane. ATP synthase (complex V) harnesses the proton gradient (proton motive force) to phosphorylate ADP to ATP—oxidative phosphorylation. One glucose yields ~30-32 ATP versus 2 from glycolysis alone, explaining why cells depend on mitochondria for most energy production.

Metabolic Regulation

Hormonal Regulation

Metabolic homeostasis is coordinated by hormones. Insulin (secreted by pancreatic beta cells after glucose ingestion) promotes glucose uptake (GLUT4 translocation in muscle and adipose), glycogen synthesis (glycogen synthase activation), glycolysis (PFK2 activation), and lipogenesis (SREBP activation) while suppressing gluconeogenesis and lipolysis. Glucagon (secreted by alpha cells during fasting) promotes glycogen breakdown, gluconeogenesis, and fatty acid mobilisation through cAMP-PKA signalling. Leptin signals adipose tissue mass to the hypothalamus regulating appetite and energy expenditure; leptin resistance in obesity disrupts satiety signalling.

Fatty Acid Metabolism

Fatty acids are a dense energy store: one palmitoyl-CoA (16C) yields ~106 ATP through beta-oxidation followed by TCA cycle and oxidative phosphorylation—more than twice the ATP per gram of glycogen. Beta-oxidation sequentially removes 2-carbon acetyl-CoA units from fatty acyl-CoA chains generating NADH and FADH2. During fasting or prolonged exercise, fatty acid oxidation in liver generates excess acetyl-CoA converted to ketone bodies (acetoacetate, beta-hydroxybutyrate)—exported as fuel for brain and muscle. Ketogenic diets exploiting this pathway have clinical utility in refractory epilepsy and are investigated for cancer metabolic targeting.

Cancer Metabolism

Cancer cells extensively reprogram metabolism even in the presence of oxygen, preferring aerobic glycolysis over oxidative phosphorylation (Warburg effect). This provides biosynthetic precursors for proliferating cells (TCA intermediates for amino acid and lipid synthesis, glucose for ribose nucleotide synthesis) at the cost of thermodynamic efficiency. Oncogenes drive metabolic reprogramming: Myc upregulates glutamine catabolism; PI3K/Akt/mTOR promotes glucose uptake and lipogenesis; HIF-1 at hypoxia transcribes glycolytic enzymes and glucose transporters. IDH1/2 mutations in AML and glioma produce 2-hydroxyglutarate, an oncometabolite inhibiting alpha-ketoglutarate-dependent dioxygenases disrupting epigenetic regulation.

Examples and Applications

Example 1: Metformin and AMPK Activation

Metformin (the world's most prescribed diabetes drug) inhibits mitochondrial complex I, lowering the ATP/AMP ratio and activating AMP-activated protein kinase (AMPK). AMPK phosphorylates ACC (inhibiting lipogenesis) and TORC2 (inhibiting gluconeogenesis) while promoting fatty acid oxidation and glucose uptake. epidemiological evidence suggests metformin reduces cancer incidence; clinical trials are testing it as an anti-ageing intervention (TAME trial). Its low cost, safety, and multi-pathway metabolic effects make it a uniquely useful therapeutic probe for metabolic biology.

Example 2: IDH Inhibitors in Cancer

IDH1 (R132H) and IDH2 (R140Q, R172K) neomorphic mutations occur in AML, glioma, and cholangiocarcinoma, producing the oncometabolite 2-hydroxyglutarate (2-HG) which inhibits alpha-KG-dependent dioxygenases including TET enzymes (DNA demethylation) and histone demethylases, causing epigenetic hypermethylation that blocks differentiation. Ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) dramatically reduce 2-HG levels in tumours, enabling differentiation of leukaemic cells—differentiation therapy echoing ATRA in APL. These targeted metabolic drugs illustrate how oncometabolite biology translates directly to mechanism-based therapy.

Example 3: Inborn Errors of Metabolism

Phenylketonuria (PKU), caused by phenylalanine hydroxylase deficiency, allows phenylalanine accumulation causing irreversible intellectual disability if untreated. Newborn screening and phenylalanine-restricted diet are highly effective. MSUD (maple syrup urine disease) causes branched-chain amino acid accumulation from BCKDH deficiency. Gaucher disease (glucocerebrosidase deficiency) causes glucosylceramide accumulation in macrophages. Enzyme replacement therapy and substrate reduction therapy treat Gaucher disease effectively. Organic acidemias and fatty acid oxidation disorders cause metabolic crises—newborn screening and metabolic formula diets prevent irreversible damage.

Example 4: Mitochondrial Diseases

Mitochondrial diseases arise from mutations in mtDNA (maternal inheritance) or nuclear genes encoding mitochondrial proteins (Mendelian inheritance). MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) carries the m.3243A>G tRNA mutation impairing translation of all mtDNA-encoded proteins. Leber hereditary optic neuropathy (LHON) arises from mtDNA complex I subunit mutations causing selective retinal ganglion cell loss and blindness. Treatment options remain limited; gene therapy delivering normal ND4 to the eye (for m.11778 LHON) entered clinical trials. Mitoplastsome and other mitochondria-targeting approaches represent emerging therapeutic frontiers.

Example 5: mTOR Signalling in Nutrient Sensing

mTOR (mechanistic target of rapamycin) complex 1 integrates growth factor signals, amino acid availability, energy status, and oxygen to regulate cell growth and autophagy. Amino acids activate Rag GTPases recruiting mTORC1 to the lysosomal surface where Rheb-GTP activates it. Active mTORC1 phosphorylates 4EBP1 and S6K1 promoting protein synthesis, ribosome biogenesis, and lipid synthesis, while suppressing autophagy. mTORC1 hyperactivation in cancer (from PI3K mutations, PTEN loss, TSC1/2 mutations) is targeted by rapalogs (everolimus) in renal cell carcinoma, breast cancer, and TSC-related tumours.

Example 6: Ketone Bodies in Epilepsy

The ketogenic diet (high fat, very low carbohydrate) induces sustained ketosis—blood ketone concentrations of 2-5 mM. In drug-resistant epilepsy (particularly in children), the ketogenic diet reduces seizure frequency in about 50% of patients, with 10-15% becoming seizure-free. Mechanisms likely include neuronal metabolic stabilisation through alternative fuel provision, altered neurotransmitter levels (increased GABA), and direct inhibition of sodium channel activity by ketone bodies. The diet is established clinical practice for refractory childhood epilepsy, with medium-chain triglyceride variants improving palatability and adherence.

Example 7: Adipose Tissue Biology

White adipose tissue stores energy as triglycerides; brown adipose tissue (BAT) and beige fat dissipate energy as heat through UCP1 (uncoupling protein 1) in the inner mitochondrial membrane, uncoupling proton gradient from ATP synthesis. Cold exposure and beta-3 adrenergic signals activate BAT thermogenesis; BAT activity inversely correlates with obesity and type 2 diabetes. BAT activation pharmacologically (through beta-3 agonists or thyroid hormone analogues) is an approach to increase energy expenditure for obesity treatment. Understanding adipose biology from receptors to transcription factors (PPARgamma is the master adipogenic regulator) has enabled the thiazolidinedione class of insulin sensitisers.

Example 8: One-Carbon Metabolism

One-carbon (1C) metabolism involves transfer of single carbon units by folate and methionine cycles, providing methyl groups for DNA methylation, histone methylation, and nucleotide synthesis. Serine, glycine, threonine, choline, and formate are 1C donors; B12 and folate are essential cofactors. Cancer cells upregulate 1C metabolism to support their elevated proliferative demands for purines and thymidylate. Methotrexate and pemetrexed inhibit dihydrofolate reductase and other 1C enzymes respectively, making them effective antiproliferative drugs. Folate supplementation prevents neural tube defects by ensuring adequate 1C metabolism during neural tube closure.

Try it live

Everything above runs in your browser — open Mitochondrial Bioenergetics Simulator and change the parameters while it is running. Nothing is installed, nothing is uploaded, the whole model lives in one tab.