Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Mitochondrial complex I (CI) deficiency is a primary cause of paediatric mitochondrial disease, often leading to severe neurological conditions like Leigh syndrome.
• Limited evidence-based treatments exist for CI deficiency, highlighting the need for novel therapeutic approaches.

Purpose of the Study:

• To investigate the efficacy of cell membrane-permeable prodrugs of succinate in restoring mitochondrial function in CI-deficient cells.
• To evaluate the potential of succinate prodrugs as a therapeutic strategy for bypassing CI defects.

Main Methods:

• Administration of succinate prodrugs to human blood cells, fibroblasts, and heart fibres with CI deficiency.
• Assessment of ATP-linked mitochondrial respiration, lactate accumulation, and lactate:pyruvate ratio.
• Utilisation of [(13)C]succinate for metabolomic analysis to confirm delivery and metabolism.

Main Results:

• Succinate prodrugs significantly increased ATP-linked mitochondrial respiration in CI-deficient cells and tissues.
• Prodrug treatment reversed lactate accumulation and alleviated the lactate:pyruvate ratio increase caused by CI inhibition.
• Metabolomic studies confirmed the intracellular delivery and metabolism of succinate.
• Respiration and spare respiratory capacity were enhanced in Leigh syndrome patient fibroblasts upon prodrug administration.

Conclusions:

• Prodrug-delivered succinate effectively bypasses mitochondrial complex I, supporting electron transport, membrane potential, and ATP production.
• This approach presents a promising therapeutic avenue for managing metabolic decompensation in mitochondrial CI dysfunction.
• Succinate prodrugs offer a potential treatment for paediatric mitochondrial diseases with CI defects.