Thymidine kinase 2 deficiency-induced mtDNA depletion in liver leads to defect beta-oxidation and insufficient supply of ketone bodies and glucose for brain function

摘要

Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA depletion syndrome for which there currently is no cure. To study the molecular mechanisms underlying the disease and search for treatment options we previously generated and described a TK2 deficient mouse strain (TK2/). The TK2/ mice were progressively hypothermic, showed no hypodermal fat layer at postnatal day 14, displayed heterogeneous adipocytes, and accumulated intracellular lipid vesicles in the liver. The attained data suggested alterations in lipid metabolism as a part of disease progression. In this study we show that the accumulation of fat vesicles in the liver cells of TK2/ mice was accompanied by increasingly hypertrophic mitochondria and depletion of mtDNA. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2/ mice. The hepatic cells of 14 days old TK2/ mice exhibited less than 20% mtDNA compared to the wild type mice and they had acquired significantly reduced mitochondrial beta-oxidation and ATP production rates. Furthermore, although the TK2/ mice of postnatal day 14 were eating, the blood sugar and the ketone levels dropped significantly compared to the levels in the wild type mice. Our hypothesis is that the gradually increasing failure of the liver to produce ketone bodies and glucose for the brain diminishes the remaining brain function and leads to loss of consciousness and ultimately death of the TK2/ mice.