Lactic acidemia in the pathogenesis of mice carrying mitochondrial DNA with a deletion

Abstract

Lactic acidemia is one manifestation of the mitochondrial diseases caused by pathogenic mutant mitochondrial DNA (mtDNA). However, little is known about its chronic effects in the progression of mitochondrial disease phenotypes. To obtain experimental evidence on this point, we used trans-mitochondrial model mice (mito-mice) heteroplasmic for wild-type and deleted mtDNA (DeltamtDNA). Mito-mice carrying predominantly DeltamtDNA showed mitochondrial respiration defects and the resultant disease phenotypes, including lactic acidemia; they also showed a decrease in mitochondrial biogenesis regulated by the peroxisome proliferative activated receptor gamma, coactivator 1 alpha (PGC1alpha)-mediated pathway, such as the expression of mitochondrial transcription factor A and mtDNA-encoded gene products and the control of mtDNA content. When the accelerated lactate production of these mito-mice was pharmacologically inhibited by sodium dichloroacetate (DCA), the decrease in mitochondrial biogenesis improved, thus leading to the relaxation of mitochondrial respiration defects and extension of life span. These results showed that chronic overproduction of lactate caused by metabolic adaptation in mitochondrial diseases further deconditioned mitochondrial function. Mitochondrial respiration defects in mitochondrial diseases are therefore induced not only directly by the presence of mutant mtDNA, but also by the chronic lactic acidemia. Our in vivo study also suggested that inhibition of chronic lactic acidemia is a potential strategy for treating some mitochondrial diseases.