Mitochondrial dysfunction inmutmethylmalonic acidemia

Abstract

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.

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

“…In the present work, we have used transgenesis to create Mut −/− mice that express Mut in hepatocytes under the control of the mouse albumin promoter (Mut −/− ;Tg INS-Alb-Mut ). These mice are protected from the neonatal lethality that characterizes the Mut −/− mice (9, 10) but manifest CTIN and a decreased glomerular filtration rate (GFR) associated with megamitochondria formation (11) and decreased cytochrome c oxidase (COX) activity in the proximal tubules. The murine studies prompted the search for similar pathology in kidney biopsies from MMA patients and suggested a therapeutic approach directed at alleviating mitochondrial dysfunction.…”

Expression of Proinflammatory Factors in Renal Cortex Induced by Methylmalonic Acid

“…18 Further, proximal and distal tubules of affected patients display functional abnormalities, including decreased reabsorption of phosphate, impaired acid-base balance, and reduced ability to concentrate urine, probably due to the presence of megamitochondria in tubular cells. 19 The participation of TI lesions in the loss of kidney function has been tacitly recognized since the development of kidney biopsy techniques made it possible to examine affected kidneys before the development of end-stage renal injury. Moreover, it was nearly four decades ago when Risdon et al 20 reported that the severity of tubular damage had a more significant correlation with the reduction of creatinine clearance than glomerular damage scores.…”

“…Rats were housed individually in metabolic cages which were placed in an air-conditioned room (18)(19)(20)(21)(22) C) with a light/dark cycle of 12 h. The study was approved by the Ethics Committee of Cruces Hospital. Animal studies were carried out in compliance with American National Institutes of Health (NIH) Principles of Laboratory Animal Care (NIH Publication 25, no.…”

Advances in high-resolution imaging – techniques for three-dimensional imaging of cellular structures

“…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.…”