Yamada Akiko, Watanabe Akira, Nara Atsushi, Inokuma Tsubasa, Asano Masatake, Shinohara Yasuo, Yamamoto Takenori
Department of Pathology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan.
Institute for Genome Research, Tokushima University, Tokushima 770-8503, Tokushima, Japan.
Int J Mol Sci. 2025 Mar 16;26(6):2670. doi: 10.3390/ijms26062670.
Mitochondrial calcium (Ca) uptake plays a key role in mitochondrial physiology and disease development. This process is regulated by the mitochondrial calcium uniporter (MCU) complex. DS16570511 is a membrane-permeable drug that inhibits mitochondrial Ca uptake, although its inhibitory mechanisms remain unclear. In this study, we evaluated the effects of DS16570511 on various mitochondrial functions through biochemical analyses. We found that DS16570511 affects multiple mitochondrial functions and exhibits variable potency in inhibiting individual processes. Specifically, DS16570511 not only inhibits MCU, its initially reported target, but also respiratory chain complexes and FF-adenosine triphosphatase/adenine nucleotide translocator, particularly respiratory chain complex II. Furthermore, the carboxyl group at the molecular terminus of DS16570511 plays a critical role in its inhibitory effects on mitochondrial Ca uptake through respiratory chain complex II inhibition. These findings enhance our understanding of the mechanisms by which DS16570511 inhibits mitochondrial Ca uptake and provide valuable insights for the clinical application of mitochondrial Ca uptake inhibitors.
线粒体钙（Ca）摄取在线粒体生理学和疾病发展中起关键作用。这一过程由线粒体钙单向转运体（MCU）复合体调控。DS16570511是一种可透过膜的药物，能抑制线粒体钙摄取，但其抑制机制尚不清楚。在本研究中，我们通过生化分析评估了DS16570511对各种线粒体功能的影响。我们发现DS16570511影响多种线粒体功能，并且在抑制各个过程中表现出不同的效力。具体而言，DS16570511不仅抑制其最初报道的靶点MCU，还抑制呼吸链复合体以及F₀F₁ - 腺苷三磷酸酶/腺嘌呤核苷酸转位酶，尤其是呼吸链复合体II。此外，DS16570511分子末端的羧基通过抑制呼吸链复合体II，在其对线粒体钙摄取的抑制作用中发挥关键作用。这些发现增进了我们对DS16570511抑制线粒体钙摄取机制的理解，并为线粒体钙摄取抑制剂的临床应用提供了有价值的见解。
