The Effects of Lipopolysaccharide Treatment on Mitochondrial Function in the POLG A449T Mouse Model

The replication of mitochondrial DNA (mtDNA) relies on holoenzyme Polymerase γ, which comprises a catalytic subunit (POLG) and two accessory subunits (POLG2). POLG mutations cause mtDNA instability, the main factor in mitochondrial diseases. My lab previously generated PolgA449T/KO mouse model reproducing the human A467T mutation. Children with POLG mutations frequently show health deterioration after experiencing their first fever. I tested if lipopolysaccharide (LPS), a bacterial toxin which induces fever in mice and humans, impacts on a PolgA449T/KO compound mouse model. Intraperitoneal injection of LPS (100 μg/kg) at 6 weeks of age caused a mild increase in body temperature, and obvious behavioral changes, in particular freezing, causing body weight loss 24 hours after the injection. Quantitative and long-range PCR analysis of mtDNA, western blot analysis of respiratory chain complexes, and spectrophotometric analysis of complex I and complex IV activity in tissue homogenates revealed that there are no significant differences between control and LPS-treated mice. These results suggest that fever is not a major driver of metabolic derangement in POLG-related disorders. However, exploring the effects of LPS treatment before post-natal day 21 (P21) can indeed provide valuable insights, considering neural development is actively occurring during this period.