Redox Modifications of Proteins of the Mitochondrial Fusion and Fission Machinery.

Christina Wolf,Eva-Maria Hanschmann,Carsten Berndt,Víctor López Del Amo,Diones Bueno,Stefan Tenzer,Axel Methner,Sabine Arndt

doi:10.3390/cells9040815

Abstract

Mitochondrial fusion and fission tailors the mitochondrial shape to changes in cellular homeostasis. Players of this process are the mitofusins, which regulate fusion of the outer mitochondrial membrane, and the fission protein DRP1. Upon specific stimuli, DRP1 translocates to the mitochondria, where it interacts with its receptors FIS1, MFF, and MID49/51. Another fission factor of clinical relevance is GDAP1. Here, we identify and discuss cysteine residues of these proteins that are conserved in phylogenetically distant organisms and which represent potential sites of posttranslational redox modifications. We reveal that worms and flies possess only a single mitofusin, which in vertebrates diverged into MFN1 and MFN2. All mitofusins contain four conserved cysteines in addition to cysteine 684 in MFN2, a site involved in mitochondrial hyperfusion. DRP1 and FIS1 are also evolutionarily conserved but only DRP1 contains four conserved cysteine residues besides cysteine 644, a specific site of nitrosylation. MFF and MID49/51 are only present in the vertebrate lineage. GDAP1 is missing in the nematode genome and contains no conserved cysteine residues. Our analysis suggests that the function of the evolutionarily oldest proteins of the mitochondrial fusion and fission machinery, the mitofusins and DRP1 but not FIS1, might be altered by redox modifications.

Highlights

The function and activity of many proteins is regulated by post-translational modifications (PTMs) of specific amino acids, including, for instance, phosphorylation of serine and tyrosine residues, ubiquitylation, and SUMOylation of lysine residues
Most of the cellular reactive species are produced by mitochondria [49,50], cellular organelles with an outer (OMM) and inner (IMM) membrane that convert most of the cell’s energy to ATP by generating a proton (∆pHm) and electrical (∆ψm) gradient across the inner membrane through the respiratory chain, which drives the ATP synthase
We here hypothesize that the cysteine modification of proteins involved in mitochondrial dynamics enables cellular adaptation to altered physiological conditions that involve reactive cellular species, and review the relevant literature on this topic

Summary

Introduction

The function and activity of many proteins is regulated by post-translational modifications (PTMs) of specific amino acids, including, for instance, phosphorylation of serine and tyrosine residues, ubiquitylation, and SUMOylation of lysine residues. *, R-SSG and RS-S alterations represent a species (RSH), to form sulfenic acid (-SOH), S-glutathionylation (R-SSG), disulphide-bonds (RS-S), diverse group of modifications All these modifications affect protein function and activity and are. 3H, which from a nucleophilic attack from HS- with already oxidized thiols, such as disulfides, glutathionylated or nitrosylated cysteines, and sulfenic acid [14]. Oxidative distress describes the pathological oxidative damage of biomolecules that has been linked to various pathologies, whereas oxidative eustress describes physiological redox alterations important for the regulation of several signaling pathways and the activity of a variety of proteins [35] For this physiological signaling function, most of the abovementioned post-translational modifications are reversible and enzymatically controlled via oxidoreductases of the thioredoxin (Trx) family (Figure 1) [36]. These enzymes are known to mediate thiol/disulfide exchange reactions, function as chaperones, and regulate protein activity [46,47,48]

The Mitochondrial Fusion and Fission Machinery

Evolutionary Conservation of Proteins Involved in Mitochondrial Dynamics

Mitofusins

Conclusions