GATD3A, a mitochondrial deglycase with evolutionary origins from gammaproteobacteria, restricts the formation of advanced glycation end products

Abstract

Background Functional complexity of the eukaryotic mitochondrial proteome is augmented by independent gene acquisition from bacteria since its endosymbiotic origins. Mammalian homologs of many ancestral mitochondrial proteins have uncharacterized catalytic activities. Recent forward genetic approaches attributed functions to proteins in established metabolic pathways, thereby limiting the possibility of identifying novel biology relevant to human disease. We undertook a bottom-up biochemistry approach to discern evolutionarily conserved mitochondrial proteins with catalytic potential. Results Here, we identify a Parkinson-associated DJ-1/PARK7-like protein—glutamine amidotransferase-like class 1 domain-containing 3A (GATD3A), with bacterial evolutionary affinities although not from alphaproteobacteria. We demonstrate that GATD3A localizes to the mitochondrial matrix and functions as a deglycase. Through its amidolysis domain, GATD3A removes non-enzymatic chemical modifications produced during the Maillard reaction between dicarbonyls and amines of nucleotides and amino acids. GATD3A interacts with factors involved in mitochondrial mRNA processing and translation, suggestive of a role in maintaining integrity of important biomolecules through its deglycase activity. The loss of GATD3A in mice is associated with accumulation of advanced glycation end products (AGEs) and altered mitochondrial dynamics. Conclusions An evolutionary perspective helped us prioritize a previously uncharacterized but predicted mitochondrial protein GATD3A, which mediates the removal of early glycation intermediates. GATD3A restricts the formation of AGEs in mitochondria and is a relevant target for diseases where AGE deposition is a pathological hallmark.

Nitrosative Stress in Astronaut Skeletal Muscle in Spaceflight

“…Previous other work with healthy subjects found elevated citrate as a potential stress response to preserve redox status of the cell during intense exercise [71] and aconitase post-translational modification as hallmarks in redox signaling and metabolism of ROS [72], further suggesting nitrosylation of mitochondrial proteins as another post-translational modification in skeletal muscle metabolism during spaceflight. Aconitase (ACOs) and oxoglutarate dehydrogenase (OGDH) inhibition via NO in rat soleus skeletal muscle strips in vitro suggests an impact of NO on catalytic enzyme functions in skeletal metabolism [73]. Mammalian GATD3 is a mitochondrial matrix enzyme with bacterial provenance that functions as a deglycase and interacts with the mitochondrial translation machinery to stabilize mitochondrial integrity involved in mitochondrial glycation status and thus dynamics [74].…”

TRPA1 channel mediates methylglyoxal-induced mouse bladder dysfunction

“…A3854, Sigma-Aldrich, Darmstadt, Germany) were diluted in basal solution containing 3% BSA. These primary antibodies were validated and tested according to previous studies (Lee et al, 2016;Jandova and Wondrak, 2021;Smith et al, 2022;Chandrakumar et al, 2023;Luostarinen et al, 2023). The antibody was incubated overnight at 4 °C, while the β-actin antibody was incubated for 1 h at room temperature.…”

Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins

“…A characteristic hallmark of DJ-1 superfamily members is the redox-sensing catalytic cysteine, whose oxidation state determines the physiological function ( Wilson, 2011 ). The emerging evidence on bacteria, humans, and plant DJ-1 members reveals a unique deglycase machinery that relieves the MG and GO glycation adducts on DNA and proteins ( Prasad et al, 2022 ; Richarme et al, 2017 ; Smith et al, 2022 ). This repair mechanism is further appreciated in preventing protein aggregation and altering the epigenetic landscape of the chromatin ( Sharma et al, 2019 ; Zheng et al, 2019 ).…”