The balancing act of NEET proteins: Iron, ROS, calcium and metabolism

Abstract

NEET proteins belong to a highly conserved group of [2Fe-2S] proteins found across all kingdoms of life. Due to their unique 2Fe-2S cluster structure, they play a key role in the regulation of many different redox and oxidation processes. In eukaryotes, NEET proteins are localized to the mitochondria, ER and the membranes connecting these organelles (MAM), and are involved in the control of multiple processes, ranging from autophagy and apoptosis to ferroptosis, oxidative stress, cell proliferation, redox control and iron and iron-sulfur homeostasis. Through their different functions and interactions with key proteins such as VDAC and Bcl-2, NEET proteins coordinate different mitochondrial, MAM, ER and cytosolic processes and functions and regulate major signaling molecules such as calcium and reactive oxygen species. Owing to their central role in cells, NEET proteins are associated with numerous human maladies including cancer, metabolic diseases, diabetes, obesity, and neurodegenerative diseases. In recent years, a new and exciting role for NEET proteins was uncovered, i.e., the regulation of mitochondrial dynamics and morphology. This new role places NEET proteins at the forefront of studies into cancer and different metabolic diseases, both associated with the regulation of mitochondrial dynamics. Here we review recent studies focused on the evolution, biological role, and structure of NEET proteins, as well as discuss different studies conducted on NEET protein function using transgenic organisms. We further discuss the different strategies used in the development of drugs that target NEET proteins, and link these with the different roles of NEET proteins in cells.

A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells

“…Aside from NAF-1(−) induced changes in mitochondria-ER MAM integrity (Figures 2 and 3), the multiple changes observed in INS-1E cells upon NAF-1 suppression recapitulate what we and others have observed in previous studies with non-endocrine cells in culture and with animal models of WFS-T2 (i.e., knockouts of NAF-1) [15,[60][61][62]. The novel finding of this work is therefore the establishment of a causative association between NAF-1 repression that leads to a mitochondrial labile iron rise and an increased mROS formation that triggers ferroptosis, and the impairment of β-cell insulin secretion.…”

“…Most of the mutations in the CISD2 gene, leading to WFS-T2, resulted in a complete or partial loss of the NAF-1 (Nutrient-deprivation Autophagy Factor-1) CISD2 protein, a protein that normally resides on the endoplasmic reticulum (ER), the outer mitochondrial membrane (OMM), and the mitochondria-ER-associated membranes (MAM) [ 12 ]. Interactome studies of NAF-1, a member of the [2Fe-2S] NEET protein family [ 13 ], implicated this protein in the regulation of autophagy and apoptosis, and added support to the empirical evidence associating NAF-1 with dysfunctional iron metabolism, ROS formation, and Ca 2+ signaling at the ER and mitochondria [ 13 , 14 , 15 ]. The association of NAF-1 function with altered iron and ROS metabolism gained further support from studies conducted in cancer cells [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET

“…We speculate that such differences may reflect their distinct biological functions; notably in the pancreas, a high level of CISD2 expression is accompanied by a low level of mitoNEET. Since both proteins are involved in the regulation of mitochondrial calcium stores through distinct mechanisms [ 27 ], the relative dependence of pancreatic cells on CISD2 for this essential regulation might help to understand why CISD2 deficiency in WFS2 patients leads to an early dysfunction of this tissue and diabetes. A similar expression profile in the spleen, where CISD2 also predominates over mitoNEET, suggests an as yet unanticipated possible involvement of CISD2 in immune cells.…”

Salusin‑β participates in high glucose‑induced HK‑2 cell ferroptosis in a Nrf‑2‑dependent manner

“…These studies indicate that oxidative stress is closely associated with both apoptosis and ferroptosis in cells. It has been indicated that ferroptosis is involved in the pathological mechanisms of numerous diseases, including diabetes, neurodegenerative diseases, atherosclerosis, obesity, non-alcoholic fatty liver disease and types of cancer ( 58 ). Notably, ferroptosis-related pathophysiological changes are also observed in DN ( 18 , 19 ).…”