DeCure for Mitochondrial pyruvate carrier deficiency

The mitochondrial pyruvate carrier was identified in yeast in 2003 by measuring inhibitor-sensitive pyruvate uptake into mitochondria from 18 different *Saccharomyces cerevisiae* mutants, each lacking an unattributed member of the mitochondrial carrier family. Only mitochondria from the YIL006w deletion mutant showed no inhibitor-sensitive pyruvate transport, but otherwise behaved normally. YIL006w encodes a 41.9 kDa protein with homologous proteins present in both the human and mouse genomes. A 2003 review noted that although the mitochondrial membrane pyruvate transporter had been characterised, its molecular identity had proved elusive, and that the identification of a single candidate protein in yeast opened the way for studies in mammalian systems.

A 2016 case report described a 32-year-old Japanese male with mitochondrial diabetes and myopathy caused by the m.14709T>C mutation. He was diagnosed with diabetes at age 20 and started insulin therapy. Water-based sodium pyruvate solutions (0.5 g/kg, thrice daily) were administered orally. His urinary C-peptide level improved from 4.3 to 17.2 μg/d after 1 day and to 30.2 μg/d after 6 months of pyruvate therapy. Total daily insulin dose decreased from 33 to 20 U/d after 6 months. The patient experienced no side effects such as diarrhoea. However, the lactate levels of plasma and cerebrospinal fluid and the lactate/pyruvate ratio did not change. The authors concluded that sodium pyruvate improved insulin secretion and resulted in decreased insulin dose in this single patient, but stated that clinical trials involving a larger number of patients and long-term evaluation are necessary.

A 2005 paper on biochemical therapy monitoring in mitochondrial encephalomyopathies stated that therapy is problematic, and that treatment involves administration of vitamins, cofactors, and modification of nutrition, such as ketogenic diet in pyruvate dehydrogenase deficiency. It noted that evaluation of the efficacy of therapeutic approaches is difficult due to the large variability of the clinical course. A 2020 systematic review on therapeutic potential of pyruvate therapy for patients with mitochondrial diseases was published, but the abstracts provided are only for its supplemental material and contain no results.

What is still missing: larger clinical trials with adequate patient numbers, long-term outcome data beyond a single case, and any evidence that pyruvate therapy affects the underlying mitochondrial defect in pyruvate carrier deficiency specifically, rather than improving insulin secretion in one patient with a different mitochondrial mutation. No trial design or patient stratification strategy for pyruvate carrier deficiency has been reported.