bims-mignad Biomed News
on Mitochondria galactose NAD
Issue of 2025–10–05
three papers selected by
Melisa Emel Ermert, Amsterdam UMC



  1. Front Pediatr. 2025 ;13 1608840
       Background: The MRPS36 gene encodes the E4 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHC), a critical enzyme in the tricarboxylic acid cycle. OGDHC deficiency can lead to metabolic disorders with a clinical spectrum ranging from fatal neonatal lactic acidosis to variable degrees of global developmental delay and movement disorders. To date, a homozygous MRPS36 variant has been reported as a novel cause of Leigh syndrome in only two siblings, who presented with developmental delay, movement disorders, bilateral striatal necrosis, and reduced OGDHC activity.
    Case presentation: We report a third case of Leigh syndrome associated with MRPS36 variants in a 2-year-old boy. The patient exhibited with global developmental delay, dystonia, early-onset chorea, and elevated serum lactate levels. Follow-up brain magnetic resonance imaging at 2 years revealed progressive degenerative lesions in the bilateral basal ganglia. Muscle biopsy showed abnormal mitochondrial accumulation beneath the sarcolemma, and the oxygen consumption rate was reduced in skin fibroblasts. Whole-exome sequencing identified two novel compound heterozygous MRPS36 variants: c.42+1G>A (p.?) and c.296G>C (p.Arg99Pro).
    Conclusion: This case supports MRPS36 as a novel pathogenic cause of Leigh syndrome, further expanding the genetic spectrum of the disorder. Key clinical features include developmental delay, involuntary movement disorders, progressive basal ganglia atrophy, and a slowly progressive disease course.
    Keywords:  2-oxoglutarate dehydrogenase complex; Leigh syndrome; MRPS36 gene; OGDHC; case report; choreic movement; movement disorder
    DOI:  https://doi.org/10.3389/fped.2025.1608840
  2. J Physiol. 2025 Oct 02.
      At rest, glucose serves as the brain's primary oxidative substrate; however, when circulating lactate is elevated, lactate oxidation increases. Whether this glucose-sparing effect differs when lactate is elevated via passive infusion versus exercise remains unknown. To address this, 13 healthy adults (six females) completed protocols of: (1) intravenous sodium lactate infusion (exogenous hyperlactataemia); and (2) cycling exercise (endogenous hyperlactataemia) to matched elevations in arterial lactate concentration (∼4 and ∼8 mmol/l). Radial arterial and internal jugular venous sampling and measures of cerebral blood flow (CBF) were used to calculate cerebral metabolic rates of glucose (CMRGlc), lactate (CMRiLac), and oxygen ( CMRO2${\mathrm{CM}}{{\mathrm{R}}_{{{\mathrm{O}}_2}}}$ ). The exogenous infusion protocol resulted in a higher CBF compared to exercise (P < 0.001), despite causing systemic alkalosis (P < 0.001). During both protocols CMRO2${\mathrm{CM}}{{\mathrm{R}}_{{{\mathrm{O}}_2}}}$ remained unchanged across increases in lactate concentrations (P = 0.610), while CMRGlc decreased (lactate, P = 0.009; condition, P = 0.373) and CMRiLac increased in a dose-dependent manner (lactate, P < 0.001; condition, P = 0.972). At an arterial concentration of 8 mmol/l, circulating lactate accounted for 24% of total cerebral oxidative metabolism. Elevated circulating lactate leads to preferential lactate oxidation and reduced glucose utilization, irrespective of whether lactate is delivered exogenously or produced endogenously. KEY POINTS: The human brain relies primarily on oxidative glucose metabolism; however, with age and in many pathologies cerebral glucose metabolism declines; therefore, there is interest in investigating alternative fuel sources that can meet the high energetic needs of the brain. The present study investigates whether increased lactate availability exerts a glucose-sparing effect in the healthy human brain, and whether this effect is consistent across physiologically distinct states of exogenous (sodium lactate infusion) and endogenous (exercise-induced) hyperlactataemia. We assessed cerebral uptake and metabolism of glucose and lactate following exercise and lactate infusion, using simultaneous arterial and jugular venous blood samples, and Duplex ultrasound. Despite stark systemic physiological differences between conditions, cerebral glucose metabolism declined in proportion to increased circulating lactate irrespective of whether it is delivered exogenously or produced endogenously. These data provide clear evidence that lactate is preferentially oxidized by the brain when made available, helping preserve glucose for non-energetic roles.
    Keywords:  cerebral lactate metabolism; cerebral substrate switch; endogenous lactate; exogenous lactate
    DOI:  https://doi.org/10.1113/JP289216
  3. Mini Rev Med Chem. 2025 Sep 29.
      Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.
    Keywords:  Mitochondria; bioenergetics; cellular signaling; metabolism; redox biology; therapeutic target.
    DOI:  https://doi.org/10.2174/0113895575403490250917111723