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靶向线粒体的肽 Elamipretide（SS-31）通过增加通过腺嘌呤核苷酸转运蛋白（ANT）的摄取来提高衰老线粒体中 ADP 的敏感性。

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).

机构信息

Department of Radiology, University of Washington, Seattle, WA, 98195, USA.

Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

出版信息

Geroscience. 2023 Dec;45(6):3529-3548. doi: 10.1007/s11357-023-00861-y. Epub 2023 Jul 18.

DOI:10.1007/s11357-023-00861-y
PMID:37462785
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10643647/
Abstract

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH (flavin adenine dinucleotide), O (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).

摘要

衰老肌肉的功能下降部分是由受损的线粒体 ADP 敏感性介导的。Elamipretide（ELAM）可迅速改善衰老过程中的生理和线粒体功能，并直接与线粒体 ADP 转运蛋白 ANT 结合。我们假设 ELAM 可改善衰老过程中 ADP 的敏感性，从而恢复生理功能。我们用 ELAM 处理来测量年轻和年老肌肉线粒体对 ADP 刺激的反应、体内心脏和肌肉功能，并比较 ADP/ATP 通路蛋白的蛋白丰度、磷酸化和 S-谷胱甘肽化。ELAM 治疗通过增加 ANT 对 ADP 的摄取来增加老年肌肉线粒体中 ADP 的敏感性，并挽救肌肉力量和心脏收缩功能。ADP/ATP 转运和合成途径中的蛋白丰度没有改变，但 ELAM 治疗可降低包括 ANT 在内的蛋白 S-谷胱甘肽化。线粒体 ADP 敏感性是可快速调节的。这项研究支持 ELAM 改善衰老过程中 ANT 功能的假说，并将线粒体 ADP 敏感性与生理功能联系起来。ELAM 直接与 ANT 和 ATP 合酶结合，ELAM 治疗可提高 ADP 敏感性、增加 ATP 生成，并改善老年肌肉的生理功能。ADP（二磷酸腺苷）、ATP（三磷酸腺苷）、VDAC（电压依赖性阴离子通道）、ANT（腺嘌呤核苷酸转运蛋白）、H（质子）、ROS（活性氧）、NADH（烟酰胺腺嘌呤二核苷酸）、FADH（黄素腺嘌呤二核苷酸）、O（氧气）、ELAM（elamipretide）、-SH（游离巯基）、-SSG（谷胱甘肽化蛋白）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a42/10643647/b8653983c173/11357_2023_861_Fig7_HTML.jpg
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