Yang Jia-Shu, Morris Andrew J, Kamizaki Koki, Chen Jianzhong, Stark Jillian, Oldham William M, Nakamura Toshitaka, Mishima Eikan, Loscalzo Joseph, Minami Yasuhiro, Conrad Marcus, Henry Whitney S, Hsu Victor W
Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Division of Cardiovascular Medicine, Department of Medicine, University of Kentucky and Lexington Veterans Affairs Medical Center, Lexington, KY 40536, USA; Central Arkansas VA Healthcare System and Arkansas Children's Nutrition Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cell. 2025 May 15;188(10):2569-2585.e20. doi: 10.1016/j.cell.2025.03.019. Epub 2025 Apr 14.
Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.
铁死亡是一种由铁诱导的脂质过氧化导致的细胞死亡形式。铁死亡抑制蛋白1（FSP1）通过生成抗氧化剂来防止这种死亡，这需要还原型烟酰胺腺嘌呤二核苷酸（NADH）作为辅因子。我们最初发现NADH在细胞膜上大量存在，随后发现这种形式的NADH由醛脱氢酶7A1（ALDH7A1）生成，以支持FSP1的活性。ALDH7A1的活性还通过消耗反应性醛类直接作用于减少脂质过氧化。此外，ALDH7A1促进FSP1的膜募集，这是由铁死亡应激激活AMP激活的蛋白激酶（AMPK）引发的，从而促进ALDH7A1的膜定位，使FSP1在膜上稳定。这些发现通过揭示细胞膜上一个以前未被认识的NADH池，推进了对NADH的基本理解，对其功能的阐明为理解FSP1的作用方式以及醛脱氢酶如何防止铁死亡提供了重要依据。
