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

ABSTRACT: 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 genetics approaches have attributed functions to proteins in established metabolic pathways limiting the possibility of identifying novel biology which may be relevant to human disease. We undertook a bottom-up biochemistry approach to identify evolutionarily conserved mitochondrial proteins with catalytic potential. Here, we identify a Parkinson-associated DJ-1/PARK7-like protein – glutamine amidotransferase-like class 1 domain containing 3A (GATD3A), with evolutionary origins from gammaproteobacteria. 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 endproducts (AGEs) and altered mitochondrial dynamics. 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. This dataset consists of FLAG co-immunoprecipitated GATD3A from Gatd3aFLAG/FLAG mouse heart left ventricular mitochondria.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Left Ventricle

SUBMITTER: Anand Swaroop  

LAB HEAD: Anand Swaroop

PROVIDER: PXD030977 | Pride | 2022-03-02

REPOSITORIES: Pride