SLC25A34 regulates bioenergetic metabolism in the murine liver

Background and Rationale Liver regeneration and diseases associated with altered mitochondrial metabolism, including NAFLD, are associated with alterations in ploidy. Many genes that regulate mitochondrial metabolism are also reported to alter hepatic polyploidy. SLC25A34 encodes an uncharacterized inner mitochondrial membrane protein, with a novel role in liver polyploidy. Interestingly, dysregulated Slc25a34 expression has been reported in numerous studies, which are all characterized by metabolic dysfunction, particularly altered glucose metabolism and fatty acid metabolism. We now hypothesize that SLC25A34 regulates various aspects of liver metabolism. Results In the current study, SLC25A34 was over expressed or knocked down in primary hepatocytes harvested from adult C57BL/6 mice and subsequent effects on different metabolic phenotypes were studied. Downregulation of SLC25A34 significantly increased the lipid droplets with a concurrent increase in expression of key players of fatty acid metabolism ( Cpt1A, Srebf1, Acly ). Maximal mitochondrial respiration and spare respiratory capacity were significantly elevated, possibly attributing to the increased levels of lipid droplets. Also, basal mitochondrial respiration and ATP‐linked mitochondrial respiration were significantly increased, accompanied by increased expression of regulators of mitochondrial biogenesis ( PGC‐1 alpha, PGC‐1 beta, Prc and Tfam ). In contrast, overexpression of SLC25A34 decreased expression of Cpt1A, Srebf1, Acly , but had no effect on lipid droplets. Unexpectedly, SLC25A34 overexpression also increased maximal mitochondrial respiration and spare respiratory capacity, as well as non‐mitochondrial respiration. Further, effect on energy intermediates (ADP, ATP and their ratio) and hepatocyte proliferation were studied. SLC25A34 depletion raised the ADP/ATP ratio and decreased hepatocyte proliferation, whereas overexpression of SLC25A34 decreased the ADP/ATP ratio and increased proliferation. Furthermore, SLC25A34 manipulation altered fatty acid oxidation and glycolysis functionally in primary hepatocytes as determined using the seahorse extracellular flux analyzer. Preliminary in‐vivo studies utilizing both whole‐body and liver‐specific SLC25A34 knockout mice indicate similar bioenergetic changes upon SLC25A34 deletion. Conclusion The data suggest that SLC25A34 is a key regulator of bioenergetic metabolism where it is involved in metabolic homeostasis and that modulation of SLC25A34 creates distinct metabolic phenotypes in the primary hepatocytes. Support or Funding Information This study is supported by NIDDKR01DK103645 and UPP Academic Foundation awarded to Dr. Andrew Wayne Duncan.