西班牙卡洛斯三世国家心血管调查中心José Antonio Enríquez和西班牙高等科学研究理事会Pablo Hernansanz-Agustín共同合作，近期取得重要工作进展。他们研究发现，跨线粒体钠梯度控制哺乳动物线粒体的膜电位。相关研究成果卡2024年9月19日在线发表于《细胞》杂志上。

据介绍，真核细胞的功能和存活依赖于线粒体H⁺电化学梯度（Δp）的使用，该梯度由线粒体内膜（IMM）电位（ΔΨmt）和pH梯度（ΔpH）组成。到目前为止，ΔΨmt被假设为完全由H⁺组成。

使用一系列线粒体和核遗传模型，研究人员发现Na⁺梯度等同于H⁺梯度，并控制着耦合呼吸哺乳动物线粒体中ΔΨmt的一半。这种平行性是由长期寻找的Na⁺特异性Na⁺/H⁺交换器（mNHE）的活性控制的，研究人员将其确定为复合物I（CI）的P模块。

Leber遗传性视神经病变（LHON）中发生这种mNHE功能的去调节，而不影响典型酶活性或CI的组装，这对ΔΨmt和线粒体Ca2⁺稳态具有深远的影响，并解释了这种神经退行性疾病以前未知的分子发病机制。

附：英文原文

Title: A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria

Author: Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez

Issue&Volume: 2024-09-19

Abstract: Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber’s hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

DOI: 10.1016/j.cell.2024.08.045

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00974-7