A Novel Role of the ASS1-CCDC6 Complex in Orchestrating Mitochondrial Dynamics to Suppress Lung Adenocarcinoma

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Abstract
The persistent high burden of lung cancer in China highlights a critical demand for the identification of new therapeutic targets and intervention approaches. Our initial integrative analysis of metabolomic and transcriptomic data revealed a previously uncharacterized tumor-suppressive mechanism mediated by CCDC6 in lung adenocarcinoma. We discovered an interaction between CCDC6 and ASS1, concomitant with marked reductions in citrulline and aspartate within tumor tissues. compared to the adjacent normal tissues. Additionally, co-stimulation with citrulline and aspartate induces ASS1 localization in the mitochondria ASS1 localized in the mitochondria, but the underlying mechanism remains unclear. This study aimed to delineate the dual tumor-suppressive actions of ASS1: firstly, through the recruitment of the deubiquitinase OTUD7A to remove ubiquitin chains from MFN1/2 and OPA1, thereby stabilizing the mitochondrial fusion machinery and inducing hyperfused network formation; and secondly, via the CCDC6-ASS1 complex, which instigates mitochondrial reactive oxygen species accumulation, compromises ATP synthesis, and reduces mitochondrial membrane potential, consequently inducing a state of metabolic dormancy in tumor cells. This study elucidates the mechanism by which the ASS1-CCDC6 axis suppresses lung adenocarcinoma progression by remodeling mitochondrial dynamics and metabolic homeostasis,, thereby establishing a theoretical basis for mitochondria-targeted precision therapy.

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