NFE2L1-mediated proteasome function protects from ferroptosis

Abstract

Objective Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood. Methods and results Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4 -deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis. Conclusion Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.

Ferroptosis and ferritinophagy in diabetes complications

“…In addition, lipid peroxidase inhibitors (such as vitamin E) can not only inhibit LOX activity, but also have weak chemical bonds to facilitate the transport of hydrogen atoms, which protect cells from ferroptosis and oxidative damage [ 64 ]. Recent studies have confirmed that transcription factor nuclear factor erythroid-2, like-1 (NFE2L1), maintains proteasome function, which reveals a new mechanism of anti-ferroptosis [ 65 ].…”

Development and validation of a novel ferroptosis‑related lncRNA prognostic signature for pancreatic adenocarcinoma

“…However, p53 can also inhibit ferroptosis by the inhibition of dipeptidyl peptidase 4 or through the enhancement of cyclin dependent kinase inhibitor 1 A ( 61 ). It has been reported that proteasome function is often inhibited during ferroptosis ( 62 ). Numerous metabolic and degradation pathways, including the ubiquitin-proteasome system, orchestrate the complex ferroptotic response through the regulation of iron accumulation or lipid peroxidation ( 63 ).…”

IF1 is a cold-regulated switch of ATP synthase to support thermogenesis in brown fat

“…Food intake and body weight were determined weekly and after the end of the adaptation period, whole-body oxygen consumption as well as CL-316,243-induced adrenergic (1 mg/kg of body weight) response was measured using indirect calorimetry. Resting and CL- 316,243-induced oxygen consumption was indirectly measured using Sable Systems Promethion Indirect Calorimetry System (Kotschi et al, 2022). For animals with IF1 overexpression in BAT (see protocol below), 3 weeks after surgery, resting oxygen consumption (VO 2 ) and carbon dioxide production (VCO 2 ) were monitored in metabolic cages (Columbus Instruments, Columbus, OH, USA) at 22 °C (Brunetta et al, 2020).…”