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Disrupting CISD2 function in cancer cells primarily alters mitochondrial labile iron status and triggers reactive oxygen species accumulation

ABSTRACT: The multiple functions of CISD2 in cells could result from its role in calcium signaling, iron and/or iron-sulfur homeostasis, and/or ROS signaling/homeostasis. The relationship(s) and interdependency between these different signaling and homeostasis processes are however unclear at present, since most studies of CISD2 to date have been conducted with cells, tissues or organisms that constitutively lack, overexpress, or contain a mutation(s) in CISD2. Although these experimental systems provided valuable information on CISD2 function, they lack a fine temporal dimension that would enable dissecting the relationship(s) between CISD2 effects on calcium, iron and ROS homeostasis and signaling. It is unclear therefore if the primary effect of CISD2 disruption results in alterations in calcium, iron, and/or ROS levels, and whether some of these alterations activate or suppress the others. To begin addressing these important questions in cancer cells, we developed an inducible system to express NAF-1 or the H114C cluster-stable mutant of NAF-1 in human epithelial breast cancer cells. Here, we report that inducible disruption of CISD2 (H114C) function in cancer cells causes an immediate disruption in mitochondrial labile iron levels and that this disruption results in altered mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mitochondrial labile iron and ROS levels took place.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ron Mittler

PROVIDER: MSV000087436 | MassIVE | Sat May 15 13:24:00 BST 2021

REPOSITORIES: MassIVE

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Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP expression.

Karmi Ola O Sohn Yang-Sung YS Zandalinas Sara I SI Rowland Linda L King Skylar D SD Nechushtai Rachel R Mittler Ron R

Free radical biology & medicine 20210920

The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring ...[more]

PMID: 34547371

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