Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species

Abstract

Aconitase, an enzyme possessing an iron-sulfur cluster that is sensitive to oxidation, is involved in the regulation of cellular metabolism. There are two isoenzymes of aconitase (Aco)--mitochondrial (mAco) and cytosolic (cAco) ones. The primary role of mAdco is believed to be to control cellular ATP production via regulation of intermediate flux in the Krebs cycle. The cytosolic Aco in its reduced form operates as an enzyme, whereas in the oxidized form it is involved in the control of iron homeostasis as iron regulatory protein 1 (IRP1). Reactive oxygen species (ROS) play a central role in regulation of Aco functions. Catalytic Aco activity is regulated by reversible oxidation of [4Fe-4S]²⁺ cluster and cysteine residues, so redox-dependent posttranslational modifications (PTMs) have gained increasing consideration as regards possible regulatory effects. These include modifications of cysteine residues by oxidation, nitrosylation and thiolation, as well as Tyr nitration and oxidation of Lys residues to carbonyls. Redox-independent PTMs such as phosphorylation and transamination also have been described. In the presence of a sustained ROS flux, redox-dependent PTMs may lead to enzyme damage and cell stress by impaired energy and iron metabolism. Aconitase has been identified as a protein that undergoes oxidative modification and inactivation in aging and certain oxidative stress-related disorders. Here we describe possible mechanisms of involvement of the two aconitase isoforms, cAco and mAco, in the control of cell metabolism and iron homeostasis, balancing the regulatory, and damaging effects of ROS.

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

“…Several regulatory mechanisms controlling respiratory fluxes have been identified. They include the modulation of the activity of key enzymes either by an inhibitory effect of high concentration of the products (Wegener and Krause, 2002;Lenzen, 2014) or by posttranslational modifications such as phosphorylation or redox regulation (Piattoni et al, 2013;Ros and Schulze, 2013;Lushchak et al, 2014;Schmidtmann et al, 2014). Our data suggest an additional regulatory feedback loop involving complex I activity.…”

Running‐wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post‐transcriptional mechanism

“…A protein that showed dominant metabolic regulation (ρ hierarchical < 0.5; p  < .05) in all four experimental groups was the TCA cycle enzyme aconitase 2 (ACO2). ACO2 is highly susceptible to oxidative damage and other post‐translational modifications due to its iron–sulphur cluster (Lushchak, Piroddi, Galli, & Lushchak, 2014). Aging increased fragmentation and protein modifications of ACO2 in rodents (Alves et al., 2010; Bota, Van Remmen, & Davies, 2002; Gannon, Staunton, O'Connell, Doran, & Ohlendieck, 2008).…”

Thiol switches in mitochondria: operation and physiological relevance

“…Numerous studies have reported the oxidative modification of aconitase and homoaconitase, which result in their inactivation during aging or in oxidative stress-related disorders (Bulteau et al, 2005). A number of recent articles indicated that the oxidative damage of aconitase might be of physiological relevance (Matasova and Popova, 2008;Lushchak et al, 2014;Stehling et al, 2014). In mammalian cells, there is a cytosolic isoform of aconitase which is also referred to as iron responsive protein that serves as transcription factor when it loses the 4Fe-4S cluster (Walden et al, 2006).…”