No conflicts of interest were declared.
Methylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathway†
Version of Record online: 18 OCT 2007
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 213, Issue 4, pages 453–461, December 2007
How to Cite
Richard, E., Alvarez-Barrientos, A., Pérez, B., Desviat, L. and Ugarte, M. (2007), Methylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathway. J. Pathol., 213: 453–461. doi: 10.1002/path.2248
- Issue online: 6 NOV 2007
- Version of Record online: 18 OCT 2007
- Manuscript Accepted: 26 AUG 2007
- Manuscript Revised: 19 AUG 2007
- Manuscript Received: 22 MAY 2007
- Ministerio de Educatioón y Ciencia, Spain. Grant Number: SAF2003-03279
- Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain. Grant Number: PI060512
- methylmalonic acidaemia;
- oxidative stress;
- flow cytometry
Methylmalonic acidaemia (MMA) is a heterogeneous group of rare genetic metabolic disorders caused by defects related to intracellular cobalamin (vitamin B12) metabolism. Increasing evidence has emerged suggesting that free radical generation is involved in the pathophysiology of neurodegenerative diseases, including some inborn errors of metabolism. We have previously identified in MMA patients several differentially expressed proteins involved in oxidative stress [mitochondrial superoxide dismutase (MnSOD) and mitochondrial glycerophosphate dehydrogenase (mGPDH)] and apoptosis by a proteomic approach. We have now extensively evaluated various parameters related to oxidative stress and apoptosis in cultured fibroblasts from a spectrum of patients with methylmalonic acidaemia. Fibroblasts from several MMA patients showed a significant increase in intracellular reactive oxygen species (ROS) content and in MnSOD expression level with respect to controls, suggesting a cellular response to intrinsic ROS stress. Moreover, we have demonstrated, using siRNA, that mGPDH is an important ROS generator in MMA patients. Cells from patients with MMA had a higher rate of apoptosis than those of controls and there was evidence that this process primarily involves the mitochondrial/caspase-dependent pathway. ROS level–phenotype correlation revealed that patients with severe neonatal cblB disorder had elevated intracellular ROS content. These findings support the possible role of oxidative stress in the pathophysiology of methylmalonic acidaemia. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.