Slc25a21, a mitochondrial carrier, transports C5-C7 oxodicarboxylates and is involved in regulating mitochondrial metabolic homeostasis [2,3]. It has a connection with the tricarboxylic acid cycle as its down-regulation can disrupt mitochondrial 2-oxoadipate transport, affecting related metabolites influx [3].

In multiple cancers, Slc25a21 shows tumor-suppressing properties. In KRAS-mutant colorectal cancer, its down-regulation promotes cancer progression. SLC25A21 depletion accelerates the growth, invasion, etc., of KRAS-mutant CRC cells, inhibits Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, and potentiates Gln replenishment for persistent KRAS activation [1]. In bladder cancer, overexpression of SLC25A21 inhibits cell proliferation, migration, and invasion, and induces apoptosis by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway [2]. In adult acute myeloid leukemia, SLC25A21 is down-regulated, and its overexpression inhibits cell proliferation, cell cycle progression, and promotes apoptosis through the mitochondrial apoptosis signaling pathway by down-regulating CXCL8 [4]. In cisplatin-induced acute kidney injury, sustaining renal Slc25a21 expression slows down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response [3].

In conclusion, Slc25a21 is crucial for maintaining mitochondrial metabolic homeostasis. Its role as a tumor suppressor in cancers like KRAS-mutant colorectal cancer, bladder cancer, and adult acute myeloid leukemia, and its function in protecting against cisplatin-induced acute kidney injury, as revealed by functional studies, provide potential therapeutic targets for these diseases.

References:

1. Hu, Sha-Sha, Han, Yue, Tan, Tian-Yuan, Ding, Yan-Qing, Wang, Shuang. 2023. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis. In JCI insight, 8, . doi:10.1172/jci.insight.167874. https://pubmed.ncbi.nlm.nih.gov/37937641/

2. Wang, Yong, Gao, Jiawen, Hu, Shasha, Chen, Hui, Wang, Shuang. 2021. SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism. In Frontiers in oncology, 11, 682710. doi:10.3389/fonc.2021.682710. https://pubmed.ncbi.nlm.nih.gov/34568013/

3. Su, Xin, Bai, Mi, Shang, Yaqiong, Chen, Huimei, Zhang, Aihua. 2024. Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis. In Cell death & disease, 15, 891. doi:10.1038/s41419-024-07231-2. https://pubmed.ncbi.nlm.nih.gov/39695098/

4. Liu, Yu, Xu, Yan, Hao, Qianqian, Yang, Lu, Wang, Shujuan. 2024. SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8. In Cell death & disease, 15, 921. doi:10.1038/s41419-024-07308-y. https://pubmed.ncbi.nlm.nih.gov/39706835/