Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J

Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The FASEB Journal (Impact Factor: 5.04). 04/2009; 23(4):1252-61. DOI: 10.1096/fj.08-121848
Source: PubMed


Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut(-/-) animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.

Download full-text


Available from: Randy J. Chandler,
  • Source
    • "Hypoglycemia, hyperammonemia and somnolence occur in many different diseases of acyl-CoA metabolism, each of which is predicted to have different abnormalities of acyl-CoA levels. The marked swelling of HLLKO liver mitochondria, particularly in samples obtained in KIC-induced crises, is similar to observations in methylmalonic acidemia, another disease of acyl-CoA metabolism for which ultrastructural data is available [29]. It will be interesting to test whether the acute crises of other inborn errors of acyl-CoA metabolism are characterized by acute reduction of acetyl-CoA and succinyl-CoA levels and by an increase in the concentration of other, potentially toxic CoAs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.
    PLoS ONE 07/2013; 8(7):e60581. DOI:10.1371/journal.pone.0060581 · 3.23 Impact Factor
  • Source
    • "This condition is known as methylmalonic acidemia, an inborn error of metabolism (IEM) with incidence of approximately 1:50,000 births (Shigematsu et al. 2002). Extracellular accumulation of MMA acts as a potent neurotoxic metabolite which causes excitotoxicity (Kolker et al. 2000), breakdown of mitochondrial energetic metabolism (Chandler et al. 2009) and oxidative stress in the central nervous system (CNS) (Fernandes et al. 2011). In line of this view, it has been demonstrated that MMA accumulation plays a role in neurological alterations including failure to thrive and psychomotor delay in patients with this organic acidemia (Manoli and Venditti 1993). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67μmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1β, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1β and TNF-α levels. Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
    Immunobiology 04/2013; 218(9). DOI:10.1016/j.imbio.2013.04.008 · 3.04 Impact Factor
  • Source
    • "One example of the application of FIB-SEM to biology is in studying conditions affecting mitochondria, such as methylmalonic acidemia (MMA), a metabolic disease that alters mitochondrial function. 2D TEM comparing normal and diseased mice has shown that MMA causes enlarged mitochondria, or megamitochondria (Chandler et al., 2009). However, such megamitochondria are only observed in tissue from older mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A fundamental goal in biology is to determine how cellular organization is coupled to function. To achieve this goal, a better understanding of organelle composition and structure is needed. Although visualization of cellular organelles using fluorescence or electron microscopy (EM) has become a common tool for the cell biologist, recent advances are providing a clearer picture of the cell than ever before. In particular, advanced light-microscopy techniques are achieving resolutions below the diffraction limit and EM tomography provides high-resolution three-dimensional (3D) images of cellular structures. The ability to perform both fluorescence and electron microscopy on the same sample (correlative light and electron microscopy, CLEM) makes it possible to identify where a fluorescently labeled protein is located with respect to organelle structures visualized by EM. Here, we review the current state of the art in 3D biological imaging techniques with a focus on recent advances in electron microscopy and fluorescence super-resolution techniques.
    Journal of Cell Science 06/2012; 125(Pt 11):2571-80. DOI:10.1242/jcs.090027 · 5.43 Impact Factor
Show more