A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria, 2024, Hernansanz-Agustín et al.

[SNT Gatchaman]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria
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

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.


Link | PDF (Cell) [Open Access]

 

[SNT Gatchaman]

The discovery that a transmitochondrial Na+ gradient controls ΔΨmt [mitochondrial membrane potential], together with its tight regulation by a non-canonical mNHE [mitochondrial complex I functions as a Na+/H+ exchanger] function of [Complex I], introduces an unexpected layer of regulation to mitochondrial bioenergetics, metabolism, and ion management in mammalian mitochondria. This activity may contribute to the versatility of mitochondrial roles found in complex organisms, in which different cell types utilize mitochondria for divergent purposes. In particular, and as shown in the present work, the generation of a transmitochondrial Na + gradient is a critical feature for mitochondrial biology, with extensive impact for neuronal physiology and disease.