Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine (M.A.W., H.C., J.R., O.V., T.M., H.P., D.D., D.R., R.T.), University of Washington, Seattle.
Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (H.C.).
Circulation. 2023 Dec 19;148(25):2038-2057. doi: 10.1161/CIRCULATIONAHA.123.066039. Epub 2023 Nov 15.
Strategies to increase cellular NAD (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation.
We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction.
We found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD level improved the function of NAD(H) redox-sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure.
These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD-based therapy for heart failure. The data also show that NAD-based therapy can be useful in pre-existing heart failure.
在多种心力衰竭模型中，增加细胞 NAD（氧化型烟酰胺腺嘌呤二核苷酸）水平的策略可预防心脏功能障碍，但分子机制尚不清楚。在心力衰竭出现症状后，基于 NAD 的治疗对衰竭心脏的益处知之甚少。大多数预处理方案提示的机制涉及激活沉默调节蛋白，特别是 Sirt3（沉默调节蛋白 3）和线粒体蛋白乙酰化。
我们通过在 SIRT3 缺陷（敲除）小鼠中施加压力超负荷来诱导心脏功能障碍，并将其与野生型小鼠的烟酰胺核糖氯化物治疗进行比较。为了模拟治疗方法，我们在已经出现心脏功能障碍的小鼠中开始治疗。
我们发现烟酰胺核糖氯化物可改善线粒体功能并阻止心力衰竭进展。在野生型和敲除型小鼠中均观察到类似的益处。提高 NAD 水平可改善 NAD（H）氧化还原敏感 SDR（短链脱氢酶/还原酶）家族蛋白的功能。多功能 SDR 蛋白和线粒体核糖核酸酶 P 亚基 Mrpp2（线粒体核糖核酸酶 P 蛋白 2）的上调可改善线粒体 DNA 转录物的加工和电子传递链功能。视黄醇代谢途径中的 SDR 激活可刺激 RXRα（视黄酸受体 α）/PPARα（过氧化物酶体增殖物激活受体 α）信号转导并恢复线粒体氧化代谢。在人类衰竭的心脏中发现 Mrpp2 下调和线粒体核糖核酸酶 P 受损，这表明在小鼠和人类心力衰竭中存在共同的缺陷线粒体生物发生机制。
这些发现将 SDR 蛋白确定为线粒体功能的重要调节剂和基于 NAD 的治疗的分子靶标。此外，无论是否通过 Sirt3 介导的线粒体蛋白去乙酰化，即基于 NAD 的心力衰竭治疗的广泛机制，都可以观察到这种益处。数据还表明，基于 NAD 的治疗在已存在的心力衰竭中可能是有用的。
