Scaf1 promotes respiratory supercomplexes and metabolic efficiency in zebrafish.

Carolina García‐Poyatos,Jesús Vázquez,Sylviane Lagarrigue,Ricardo Magni,Xavier Langa,Pablo Hernansanz‐Agustín,Marius Botos,Nadia Mercader,José Antonio Enríquez,Sara Cogliati,Enrique Calvo,Francesca Amati

doi:10.15252/embr.202050287

Carolina García‐Poyatos, Jesús Vázquez + Show 10 more

Open Access

https://doi.org/10.15252/embr.202050287

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Abstract

The oxidative phosphorylation (OXPHOS) system is a dynamic system in which the respiratory complexes coexist with super‐assembled quaternary structures called supercomplexes (SCs). The physiological role of SCs is still disputed. Here, we used zebrafish to study the relevance of respiratory SCs. We combined immunodetection analysis and deep data‐independent proteomics to characterize these structures and found similar SCs to those described in mice, as well as novel SCs including III 2 + IV 2, I + IV, and I + III 2 + IV 2. To study the physiological role of SCs, we generated two null allele zebrafish lines for supercomplex assembly factor 1 (scaf1). scaf1 −/− fish displayed altered OXPHOS activity due to the disrupted interaction of complexes III and IV. scaf1 −/− fish were smaller in size and showed abnormal fat deposition and decreased female fertility. These physiological phenotypes were rescued by doubling the food supply, which correlated with improved bioenergetics and alterations in the metabolic gene expression program. These results reveal that SC assembly by Scaf1 modulates OXPHOS efficiency and allows the optimization of metabolic resources.

Highlights

In the last 2 years, the focus of investigation on the structure of the mitochondrial electron transport chain (ETC) has shifted from the dispute over the existence of supercomplexes (SCs) to their putative functional role
We first characterized the pattern of respiratory complex super-assembly in adult zebrafish using 1D and two-dimensional (2D) blue native gel electrophoresis (BNGE) as well as Blue-data-independent scanning (DiS)-based proteomics
We show that a lack of Scaf1-mediated complexes III (CIII)-CIV superassembly impairs the bioenergetic efficiency of the ETC and leads to non-pathological physiological alterations at the organismal level

Summary

Introduction

In the last 2 years, the focus of investigation on the structure of the mitochondrial electron transport chain (ETC) has shifted from the dispute over the existence of supercomplexes (SCs) to their putative functional role. The super-assembly between CIII and CIV allows the control of available CIV through compartmentalization Both functions optimize the metabolic flux, preventing an electron traffic jam [1] and minimizing reactive oxygen species (ROS) production [10] while maintaining an efficient energy production [9]. The phenotypic rescue occurred in the absence of a recovery of OXPHOS super-assembly and correlated with alterations in the metabolic gene expression program. Overall, these results confirm a role for SCs in the efficiency of the respiratory chain in a vertebrate animal model and reveal that SCs provide an advantage in the optimization of metabolic resources

Results

Site specific mitochondria uncoupled respiration

Discussion

Materials and Methods

Data and code availability