DS16570511 is a cell-permeable mitochondrial calcium uniporter inhibitor with an IC50 value of 7μM for channel blockade[1]. Calcium entry into mitochondria is mediated by a highly selective calcium channel, called the mitochondrial calcium uniporter, which consists of a pore-forming subunit, MCU, and regulatory subunits such as MICU1[2]. DS16570511 can inhibit respiratory chain complexes and FoF1-ATPase/adenine nucleotide translocator, particularly respiratory chain complex II[3].
In vitro, treatment of HEK293A cells with DS16570511 (0-30μM) for 20min inhibited Ca2+ uptake in isolated mitochondria[4]. Treatment of neurons with DS16570511 (30, 45μM) attenuated the occurrence of glutamate-induced delayed calcium dysregulation in neurons and inhibited cell death[5]. Treatment of vitrified MII oocytes with DS16570511 (8µM) reduced intracellular mitochondrial membrane potential, phosphorylated pyruvate dehydrogenase (p-PDH), and ATP levels[6].
References:
[1] Payne R, Li C, Fernandez-Garcia E, et al. The MCU inhibitor Ds16570511 has off-target effects on mitochondrial membrane potential[J]. Biophysical Journal, 2019, 116(3): 270a.
[2] Kamer K J, Mootha V K. The molecular era of the mitochondrial calcium uniporter[J]. Nature reviews Molecular cell biology, 2015, 16(9): 545-553.
[3] Yamada A, Watanabe A, Nara A, et al. Multiple Inhibitory Mechanisms of DS16570511 Targeting Mitochondrial Calcium Uptake: Insights from Biochemical Analysis of Rat Liver Mitochondria[J]. International Journal of Molecular Sciences, 2025, 26(6): 2670.
[4] Kon N, Murakoshi M, Isobe A, et al. DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter[J]. Cell death discovery, 2017, 3(1): 1-7.
[5] Belosludtsev K N, Sharipov R R, Boyarkin D P, et al. The effect of DS16570511, a new inhibitor of mitochondrial calcium uniporter, on calcium homeostasis, metabolism, and functional state of cultured cortical neurons and isolated brain mitochondria[J]. Biochimica et Biophysica Acta (BBA)-General Subjects, 2021, 1865(5): 129847.
[6] Lan T, Zhang K, Lin F, et al. Effects of MICU1-mediated mitochondrial calcium uptake on energy metabolism and quality of vitrified-thawed mouse metaphase II oocytes[J]. International Journal of Molecular Sciences, 2022, 23(15): 8629.
DS16570511是一种具有细胞渗透性的线粒体钙单向转运体抑制剂，通道阻滞的IC50值为7μM[1]。钙离子进入线粒体是由一种高选择性的钙离子通道介导的，称为线粒体钙单向转运体，它由一个成孔亚基MCU和调节亚基如MICU1组成[2]。DS16570511能够抑制呼吸链复合物和FoF1-腺苷三磷酸酶/腺嘌呤核苷酸转运蛋白，特别是呼吸链复合物II[3]。
在体外，DS16570511（0-30µM）处理HEK293A细胞20min，抑制了细胞分离线粒体中的Ca2+摄取[4]。DS16570511（30, 45µM）处理神经元细胞，减缓了谷氨酸诱导的神经元延迟钙失调的发生，抑制了细胞的死亡[5]。DS16570511（8µM）处理玻璃化冷冻后MII期卵母细胞，降低了细胞内线粒体膜电位、磷酸化丙酮酸脱氢酶（p-PDH）和ATP水平[6]。