SLC25A mitochondrial carriers as biomarkers and therapeutic targets of spaceflight-induced dysfunction: the ADP/ATP carrier (AAC3) as a structural case study

Background: Spaceflight exposes living organisms to mechanical unloading and cosmic radiation that profoundly reshape metabolism and tissue function. Because mitochondria play a crucial role in dealing with stress responses, members of the SLC25A carrier family become crucial checkpoints for controlling cellular energy and redox homeostasis. Methods: In this study, we examined the expression of 53 SLC25A genes across osteocytes, human bone marrow-derived mesenchymal stem cells (hBMSCs), and mouse brain under microgravity, using curated transcriptomic datasets from NASAs Open Science Data Repository (OSDR). In addition, given that ADP/ATP carriers (AACs) are key mediators of apoptosis, we further investigated AACs through structural modeling and molecular docking with the specific pro-apoptotic (carboxyatractyloside) and anti-apoptotic (bongkrekic acid) inhibitors, with the aim of proposing them as potential targets for apoptosis regulation. Results: Our analysis reveals distinct, tissue-specific expression patterns, with bone cells showing early alteration of the expression of mitochondrial transporters, with enhanced levels of AAC4, CFNc, GC1, CIC, and PNC2, together with reduced UCP2, OGC, and AGC2. These alterations indicate an impaired metabolite transport and gradual metabolic adaptation. hBMSCs, by contrast, repressed AGC1, CAC, UCP6, ORC1, and GlyC, while increasing AAC3, MFRN1, and SLC25A40 expression, consistently with weaker oxidative phosphorylation and limited renewal potential. Brain tissue appeared comparatively resilient, displaying only a selective rise in DIC, most likely reflecting adaptive activation of dicarboxylate flux. Structural modeling of AACs highlighted conserved conformational features that can be exploited for the structural modeling of all mitochondrial carriers, thereby providing a foundation for the design of drugs targeting all members of the SLC25A family and for the development of selective modulators capable of restoring apoptosis control and mitochondrial function during exposure to microgravity or cosmic radiation. Conclusions: The presented results establish SLC25A carriers as biomarkers and potential therapeutic targets for counteracting bone/muscle loss, mitochondrial dysfunction, and neurodegeneration under space conditions. By integrating transcriptomic analysis with structural modeling, this work provides translational relevance for astronaut health and offers mechanistic insights applicable to terrestrial mitochondrial disorders as well.