Constraint-based modeling of yeast mitochondria reveals the dynamics of protein import and iron-sulfur cluster biogenesis

Carl Malina,Francesca Di Bartolomeo,Eduard J Kerkhoven,Jens Nielsen

doi:10.1016/j.isci.2021.103294

Carl Malina, Francesca Di Bartolomeo + Show 2 more

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https://doi.org/10.1016/j.isci.2021.103294

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Abstract

SummaryMitochondria are a hallmark of eukaryal cells and play an important role in cellular metabolism. There is a vast amount of knowledge available on mitochondrial metabolism and essential mitochondrial functions, such as protein import and iron-sulfur cluster biosynthesis, including multiple studies on the mitochondrial proteome. Therefore, there is a need for in silico approaches to facilitate the analysis of these data. Here, we present a detailed model of mitochondrial metabolism Saccharomyces cerevisiae, including protein import, iron-sulfur cluster biosynthesis, and a description of the coupling between charge translocation processes and ATP synthesis. Model analysis implied a dual dependence of absolute levels of proteins in protein import, iron-sulfur cluster biogenesis and cluster abundance on growth rate and respiratory activity. The model is instrumental in studying dynamics and perturbations in these processes and given the high conservation of mitochondrial metabolism in humans, it can provide insight into their role in human disease.

Highlights

Mitochondria are a hallmark of eukaryal cells and essential for their viability
SUMMARY Mitochondria are a hallmark of eukaryal cells and play an important role in cellular metabolism
There is a vast amount of knowledge available on mitochondrial metabolism and essential mitochondrial functions, such as protein import and iron-sulfur cluster biosynthesis, including multiple studies on the mitochondrial proteome

Summary

Introduction

Mitochondria are a hallmark of eukaryal cells and essential for their viability. Being the center of oxidative phosphorylation, they are often referred to as the powerhouses of the cell, but mitochondria are central to other parts of cellular metabolism and signaling (Malina et al, 2018). Mitochondrial proteomics studies have identified a large fraction of the mitochondrial proteome (Reinders et al, 2006; Sickmann et al, 2003; Vogtle et al, 2012; Vogtle et al, 2017; Zahedi et al, 2006), elucidating numerous mitochondrial functions beyond energy metabolism. These functions include protein import (Wiedemann and Pfanner, 2017) and synthesis of iron-sulfur (Fe/S) clusters (Lill and Freibert, 2020), both essential for cell viability under all conditions. The only moderately altered expression poses a challenge when it comes to experimentally determining the actual levels of proteins involved in Fe/S cluster generation and protein import required to sustain functional mitochondria

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