Mitochondrial dysfunction in methylmalonic acidemia: a pilot study using Seahorse technology in peripheral blood

Abstract

Introduction: Isolated methylmalonic acidemia (MMA) is an inborn error of metabolism due to the deficiency of the methylmalonic mutase enzyme. Many patients develop chronic complications such as basal ganglia lesions or kidney impairment. A growing body of evidence supports secondary mitochondrial dysfunction as the main cause for the development of these long-term complications, even in patients with good metabolic control. Currently, available methods to study mitochondrial function are often invasive, such as muscular or skin biopsy. Objectives: This pilot study is aimed to develop a safe, non-invasive method to assess mitochondrial and glycolytic function in isolated MMA patients using lymphocytes. Materials and methods: Mitochondrial bioenergetics and glycolysis were evaluated in lymphocytes from two mut0 MMA patients and two age- and sex-matched controls using Seahorse technology. In vitro treatments with triheptanoin, citrate, and resveratrol were performed. Results: MMA lymphocytes showed significant impairment in mitochondrial respiration and glycolysis compared to healthy controls. Triheptanoin exposure improved ATP production and glycolytic flux (ECAR), but no significant changes were observed in oxygen consumption (OCR). Citrate and resveratrol had no measurable impact on bioenergetic parameters. Conclusions: This exploratory study suggests that Seahorse technology can detect mitochondrial dysfunction in MMA lymphocytes. Further studies in larger cohorts are required to validate these findings and explore their clinical relevance.