Mitochondrial Carrier Transport Mechanisms in Metabolic Disorders

The family of mitochondrial carrier proteins orchestrates the regulated exchange of metabolites, nucleotides and cofactors across the inner mitochondrial membrane, a process fundamental to cellular energy homeostasis. Dysfunctions in these carriers, arising from genetic mutations or regulatory perturbations, underlie a spectrum of metabolic disorders characterised by impaired ATP production, redox imbalances and substrate accumulation. Key subfamilies, including the ADP/ATP carrier, phosphate carrier and aspartate/glutamate carriers, employ a conserved alternating-access mechanism to shuttle substrates, while regulatory domains laden with calcium-binding motifs modulate transport in response to cellular signals. Pathogenic variants in solute carrier family 25 members manifest as encephalopathies, myopathies and hepatopathies, driven by altered mitochondrial respiration, oncometabolite build-up and chronic stress responses. Emerging insights into carrier structure, gating dynamics and compensatory metabolic rewiring inform strategies for diagnosis and targeted interventions in these multifaceted diseases.

Research from Nature Portfolio

Recent structural analyses of calcium-induced conformational changes in mitochondrial aspartate/glutamate carriers have elucidated how binding to EF-hand domains regulates vestibule opening and substrate access, providing a molecular framework for understanding citrin deficiency. Complementary population-scale genetic studies have expanded the mutation spectrum of the SLC25A13 gene in neonatal intrahepatic cholestasis, revealing distinct geographic patterns and informing refined diagnostic approaches across diverse cohorts.

Mitochondrial Carrier Transport Mechanisms in Metabolic Disorders publication trend

The graph below shows the total number of articles in mitochondrial carrier transport mechanisms in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Solute carrier family 25 (SLC25): A group of inner mitochondrial membrane proteins that transport metabolites, nucleotides and cofactors between the matrix and cytosol.

Alternating-access mechanism: A model in which a carrier protein alternates exposure of its central substrate-binding site to either side of the membrane through coordinated gate movements.

ADP/ATP carrier: A subtype of SLC25 proteins that exchanges cytosolic ADP for mitochondrial ATP to sustain cellular energy balance.

Senescence: A state of permanent cell-cycle arrest triggered by stress or damage, accompanied by specific metabolic and transcriptional changes.

2-Hydroxyglutarate: An oncometabolite whose aberrant accumulation disrupts cellular metabolism and redox balance, implicated in certain mitochondrial disorders.

References

1. The SLC25 Mitochondrial Carrier Family: Structure and Mechanism. Trends in Biochemical Sciences (2019).
2. Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. Nature Communications (2014).
3. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution. Scientific Reports (2016).
4. Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53. Cell Death & Differentiation (2024).
5. Metabolic impact of genetic and chemical ADP/ATP carrier inhibition in renal proximal tubule epithelial cells. Archives of Toxicology (2023).
6. Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review. Biomolecules (2020).