Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase γ (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study

Abstract

Combined morphological, immunocytochemical, biochemical and molecular genetic studies were performed on skeletal muscle, heart muscle and liver tissue of a 16-months boy with fatal liver failure. The pathological characterization of the tissues revealed a severe depletion of mtDNA (mitochondrial DNA) that was most pronounced in liver, followed by a less severe, but still significant depletion in skeletal muscle and the heart. The primary cause of the disease was linked to compound heterozygous mutations in the polymerase γ (POLG) gene (DNA polymerase γ; A467T, K1191N). We present evidence, that compound heterozygous POLG mutations lead to tissue selective impairment of mtDNA replication and thus to a mosaic defect pattern even in the severely affected liver. A variable defect pattern was found in liver, muscle and heart tissue as revealed by biochemical, cytochemical, immunocytochemical and in situ hybridization analysis. Functionally, a severe deficiency of cytochrome-c-oxidase (cox) activity was seen in the liver. Although mtDNA depletion was detected in heart and skeletal muscle, there was no cox deficiency in these tissues. Depletion of mtDNA and microdissection of cox-positive or negative areas correlated with the histological pattern in the liver. Interestingly, the mosaic pattern detected for cox-activity and mtDNA copy number fully aligned with the immunohistologically revealed defect pattern using Pol γ, mtSSB- and mtTFA-antibodies, thus substantiating the hypothesis that nuclear encoded proteins located within mitochondria become unstable and are degraded when they are not actively bound to mtDNA. Their disappearance could also aggravate the mtDNA depletion and contribute to the non-homogenous defect pattern.

Mitochondrial (dys)function – a factor underlying the variability of efavirenz‐induced hepatotoxicity?

“…Although the threshold level can partly explain the disease phenotypes and clinical severity observed in patients, an exact correlation is lacking. Mitochondrial diseases with a major hepatic component (hepatocerebral mtDNA depletion syndromes or isolated hepatic disease) display a significant decrease in liver mtDNA content with most cases usually presenting 20% or less mtDNA compared with age‐matched healthy control individuals (Dimmock et al ., ; Müller‐Höcker et al ., ). It is generally assumed that in mtDNA‐depleted cells, the reduced abundance of mtDNA‐encoded proteins mirrors the replicative failure of mtDNA.…”

Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish

“…Finally, taking advantage of fluorescent transgenes and birefringence properties in the zebrafish organism, we investigated the morphology of liver and skeletal muscle, two of the most affected tissues in Polg-related disease 25 . For liver analysis, we measured the fluorescence of liver-specific transgenic zebrafish at 8 and 16 dpf (Fig.…”

Anin situatlas of mitochondrial DNA in mammalian tissues reveals high content in stem/progenitor cells

“…These include inherited autosomal and mtDNA syndromes that affect mtDNA copy number 74 that involve a number of organ systems and cell types (e.g. involving skeletal and cardiac muscle, neurons in Parkinson's disease and other neurodegenerative disorders, hepatocytes in liver, etc.).…”