Major achievements

In 2007 high resolution two-dimensional PAGE of mitochondrial preparations from young and senescent human umbilical vein endothelial cells (HUVEC) were prepared using the ProteoTope™ technique. This revealed an age-related difference in isoelectric point of about 0.4 pI units for two protein spots, suggesting differences in post-translational modification of the associated protein with cellular senescence. Mass spectrometric analysis identified the protein as fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1). In 2011 and 2015, Pircher et al. were able to identify FAHD1 as acylpyruvate hydrolase (ApH) and oxaloacetate decarboxylase (ODx), which is localized in mitochondria and belongs to the broad FAH superfamily of enzymes. The localization of FAHD1 in mitochondria and its ODx activity rendered a model of FAHD1 acting as regulator of oxaloacetate levels in the TCA cycle, which was accompanied by the description of the FAHD1 catalytic mechanism. Work with the model organism Caenorhabditis elegans provided first support for this hypothesis, as deletion of fahd-1 induced severe mitochondrial dysfunction and impaired locomotion activity. Recent work linked FAHD-1 activity to serotonin signaling in the nematode. Work with HUVEC displayed that depletion of FAHD1 inhibits mitochondrial ETC and induces cellular senescence in human endothelial cells. This enabled the hypothesis of FAHD1 being a regulator of cellular senescence via regulation of the mitochondrial ETC in the context of mitochondrial dysfunction associated senescence (MiDAS) described previously by us and others.In 2007 high resolution two-dimensional PAGE of mitochondrial preparations from young and senescent human umbilical vein endothelial cells (HUVEC) were prepared using the ProteoTope™ technique. This revealed an age-related difference in isoelectric point of about 0.4 pI units for two protein spots, suggesting differences in post-translational modification of the associated protein with cellular senescence. Mass spectrometric analysis identified the protein as fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1). In 2011 and 2015, Pircher et al. were able to identify FAHD1 as acylpyruvate hydrolase (ApH) and oxaloacetate decarboxylase (ODx), which is localized in mitochondria and belongs to the broad FAH superfamily of enzymes. The localization of FAHD1 in mitochondria and its ODx activity rendered a model of FAHD1 acting as regulator of oxaloacetate levels in the TCA cycle, which was accompanied by the description of the FAHD1 catalytic mechanism. Work with the model organism Caenorhabditis elegans provided first support for this hypothesis, as deletion of fahd-1 induced severe mitochondrial dysfunction and impaired locomotion activity. Recent work linked FAHD-1 activity to serotonin signaling in the nematode. Work with HUVEC displayed that depletion of FAHD1 inhibits mitochondrial ETC and induces cellular senescence in human endothelial cells. This enabled the hypothesis of FAHD1 being a regulator of cellular senescence via regulation of the mitochondrial ETC in the context of mitochondrial dysfunction associated senescence (MiDAS) described previously by us and others.
Oxaloacetate decarboxylases are mainly known from prokaryotic organisms, where membrane-bound and soluble variants exist. The membrane-bound variants generally depend on sodium ions and biotin, whereas the soluble variants depend on bivalent metal cations. The described eukaryotic members of the FAH superfamily are FAH, FAHD1, and FAHD2. FAHD1 differs from FAH in its physical properties, localization, and rather low catalytic activity. The postulated mechanism for FAHD1 catalytic activity was substantiated by experimental data. The bi-functionality of FAHD1, acting as ApH and ODx, even raised the idea of the eukaryotic FAHD1 being a hybrid of related prokaryotic precursor proteins. However, the exact role of FAHD proteins, and of FAHD1 in particular, is not fully revealed to date.