bims-mitpro 2024-05-19 papers

Issue of 2024‒05‒19
two papers selected by
Andreas Kohler, Umeå University

Aging Dis. 2024 Apr 25.

The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.

S-Nitrosylation is a reversible covalent post-translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post-translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant S- nitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.

DOI: https://doi.org/10.14336/AD.2024.0099

Proc Natl Acad Sci U S A. 2024 May 21. 121(21): e2400740121

Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol.

Joseph J Braymer, Oliver Stehling, Martin Stümpfig, Ralf Rösser, Farah Spantgar, Catharina M Blinn, Ulrich Mühlenhoff, Antonio J Pierik, Roland Lill.

The biogenesis of iron-sulfur (Fe/S) proteins entails the synthesis and trafficking of Fe/S clusters, followed by their insertion into target apoproteins. In eukaryotes, the multiple steps of biogenesis are accomplished by complex protein machineries in both mitochondria and cytosol. The underlying biochemical pathways have been elucidated over the past decades, yet the mechanisms of cytosolic [2Fe-2S] protein assembly have remained ill-defined. Similarly, the precise site of glutathione (GSH) requirement in cytosolic and nuclear Fe/S protein biogenesis is unclear, as is the molecular role of the GSH-dependent cytosolic monothiol glutaredoxins (cGrxs). Here, we investigated these questions in human and yeast cells by various in vivo approaches. [2Fe-2S] cluster assembly of cytosolic target apoproteins required the mitochondrial ISC machinery, the mitochondrial transporter Atm1/ABCB7 and GSH, yet occurred independently of both the CIA system and cGrxs. This mechanism was strikingly different from the ISC-, Atm1/ABCB7-, GSH-, and CIA-dependent assembly of cytosolic-nuclear [4Fe-4S] proteins. One notable exception to this cytosolic [2Fe-2S] protein maturation pathway defined here was yeast Apd1 which used the CIA system via binding to the CIA targeting complex through its C-terminal tryptophan. cGrxs, although attributed as [2Fe-2S] cluster chaperones or trafficking proteins, were not essential in vivo for delivering [2Fe-2S] clusters to either CIA components or target apoproteins. Finally, the most critical GSH requirement was assigned to Atm1-dependent export, i.e. a step before GSH-dependent cGrxs function. Our findings extend the general model of eukaryotic Fe/S protein biogenesis by adding the molecular requirements for cytosolic [2Fe-2S] protein maturation.

Keywords: cytosolic iron-sulfur protein assembly (CIA); glutaredoxin; glutathione (GSH); iron homeostasis; iron-sulfur cluster assembly (ISC)

DOI: https://doi.org/10.1073/pnas.2400740121