Mitochondrial Metabolism and Regulation in Mammalian Systems

Mitochondria are central hubs for energy production, intermediary metabolism and cellular signalling in mammalian cells. Through oxidative phosphorylation, they convert substrates derived from carbohydrates, lipids and amino acids into ATP, while concomitantly generating reducing equivalents that regulate redox homeostasis. The tricarboxylic acid (TCA) cycle not only supplies electrons to the respiratory chain but also provides precursors for biosynthetic pathways, including amino acids and lipid backbones. Mitochondrial function is fine-tuned by a network of feedback loops involving substrate availability, post-translational modification of key enzymes and dynamically regulated protein complexes known as respiratory supercomplexes. Calcium uptake into the matrix coordinates energy demand with ATP production, while reactive oxygen species produced as by-products act as signalling molecules, modulating gene expression and stress responses. Perturbations in mitochondrial metabolism underpin a wide spectrum of pathologies, from metabolic syndrome and neurodegeneration to cancer. Recent advances in high-resolution structural biology, live-cell imaging and multi-omics profiling have deepened our understanding of the molecular mechanisms governing mitochondrial dynamics, organelle quality control and inter-organelle communication. These insights pave the way for novel therapeutic strategies targeting mitochondrial bioenergetics and signalling in human disease.

Research from Nature Portfolio

Recent studies have elucidated the structural basis of respiratory supercomplex assembly, revealing how specific lipid environments stabilise interactions between Complexes I, III and IV to optimise electron flux and minimise reactive oxygen species generation. Advanced cryo-electron microscopy has captured distinct conformational states that correlate with substrate-induced changes in proton-pumping efficiency. Complementary proteomic analyses have mapped a dynamic phosphorylation landscape across the TCA cycle and oxidative phosphorylation machinery, identifying kinases that respond to nutrient availability and stress. In parallel, live-cell fluorescence imaging of genetically encoded calcium sensors has demonstrated how transient mitochondrial calcium uptake synchronises ATP synthesis with cytosolic signalling cascades during muscle contraction and neuronal activity. These investigations underscore a coordinated regulatory network that integrates metabolic flux, post-translational modification and organelle crosstalk to maintain cellular energy homeostasis.

Mitochondrial Metabolism and Regulation in Mammalian Systems publication trend

The graph below shows the total number of articles in mitochondrial metabolism and regulation in mammalian systems across all publications each year (not limited to Nature Index journals).

Technical terms

Oxaloacetate: A four-carbon TCA cycle intermediate that regulates citrate synthase and links gluconeogenesis to energy status.

Respiratory supercomplex: Supramolecular assemblies of multiple respiratory chain complexes that enhance electron transfer efficiency and reduce reactive oxygen species.

Malate–aspartate shuttle: A biochemical pathway transferring reducing equivalents from cytosolic NADH into the mitochondrial matrix via sequential transamination and transport steps.

Mitochondrial membrane potential: The electrochemical gradient across the inner mitochondrial membrane that drives ATP synthesis and metabolite transport.

Reactive oxygen species: Chemically reactive molecules derived from oxygen, produced as by-products of respiration and involved in redox signalling and stress responses.

References

1. Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential‐dependent accumulation. The FASEB Journal (2025).
2. Control Mechanisms of Gluconeogenesis and Ketogenesis II. Interactions between fatty acid oxidation and the citric acid cycle in perfused rat liver. Journal of Biological Chemistry (1969).