Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, MSC0610, 6 Center Drive, Bethesda, MD, 20892, USA.
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.
BMC Biol. 2022 Mar 21;20(1):68. doi: 10.1186/s12915-022-01267-6.
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.
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.
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.
自真核生物线粒体起源的内共生事件以来，通过从细菌中独立获得基因，其蛋白质组的功能复杂性得到了增强。许多祖先线粒体蛋白的哺乳动物同源物具有未被表征的催化活性。最近的正向遗传学方法将功能归因于既定代谢途径中的蛋白质，从而限制了识别与人类疾病相关的新生物学的可能性。我们采用自下而上的生物化学方法来识别具有催化潜力的进化保守的线粒体蛋白。
在这里，我们鉴定出一种与帕金森病相关的 DJ-1/PARK7 样蛋白-谷氨酰胺酰胺转移酶样 1 类结构域包含 3A（GATD3A），尽管它与α变形菌没有进化关系，但具有细菌进化关系。我们证明 GATD3A 定位于线粒体基质中，作为去糖基酶发挥作用。通过其酰胺水解酶结构域，GATD3A 去除二羰基化合物和核苷酸及氨基酸的胺之间美拉德反应产生的非酶化学修饰。GATD3A 与参与线粒体 mRNA 加工和翻译的因子相互作用，表明其通过去糖基酶活性在维持重要生物分子的完整性方面发挥作用。在小鼠中丢失 GATD3A 与晚期糖基化终产物 (AGE) 的积累和线粒体动力学的改变有关。
从进化角度出发，帮助我们确定了一个以前未被表征但预测的线粒体蛋白 GATD3A，它介导早期糖化中间产物的去除。GATD3A 限制了 AGE 在线粒体中的形成，是 AGE 沉积作为病理标志的疾病的相关靶点。
