{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC25A51 was recently identified as the long‐sought mammalian mitochondrial NAD+ transporter responsible for importing intact NAD+ into the mitochondrial matrix. Experimental evidence demonstrates that loss of SLC25A51 leads to a specific depletion of mitochondrial NAD+, impaired respiration, and other bioenergetic defects, while its overexpression restores NAD+ uptake and mitochondrial function. Genetic interaction studies and large‐scale functional screens further implicated SLC25A51 in maintaining mitochondrial respiration and redox homeostasis, thereby resolving a longstanding mystery in NAD+ biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent mechanistic studies using molecular dynamics simulations have begun to elucidate how SLC25A51 overcomes the conformational and electrostatic challenges of translocating such a large, charged coenzyme. Specific cardiolipin binding sites and a critical salt bridge control the formation of a gate that is altered upon NAD+ binding, thereby initiating the transport process. In addition, loss of SLC25A51 has been found to perturb subcellular NAD+ distribution, leading to elevated cytoplasmic and nuclear NAD+ levels that enhance PARP1‐mediated ADP‐ribosylation and accelerate DNA repair responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of disease, SLC25A51 emerges as a critical player in cellular metabolism and a potential therapeutic target. It is upregulated in several cancers, including acute myeloid leukemia (AML), where increased transporter levels support oxidative metabolic pathways that fuel cell proliferation. Alterations in SLC25A51 function affect mitochondrial NAD+ levels, protein acetylation via SIRT3, and even key biosynthetic reactions such as proline production, thereby modulating the sensitivity of cancer cells to agents like PARP inhibitors and suggesting combinatorial strategies for therapy. Furthermore, a deeper understanding of its multi‐tiered regulation underscores the pivotal role of SLC25A51 in coordinating mitochondrial and cellular metabolic homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Timothy S Luongo, Jared M Eller, Mu-Jie Lu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Dynamics of SLC25A51 reveal preference for oxidized NAD"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " and substrate led transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.202256596"}], "href": "https://doi.org/10.15252/embr.202256596"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37575034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37575034"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Anka Güldenpfennig, Ann-Katrin Hopp, Lukas Muskalla, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41418-023-01185-2"}], "href": "https://doi.org/10.1038/s41418-023-01185-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37419986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37419986"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shivansh Goyal, Xiaolu A Cambronne "}, {"type": "b", "children": [{"type": "t", "text": "Layered mechanisms regulating the human mitochondrial NAD+ transporter SLC25A51."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST20220318"}], "href": "https://doi.org/10.1042/BST20220318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38108469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38108469"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, et al. 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