Jin Ye Lab

Research

Molecular mechanism of ferroptosis in development of human diseases

Our cells need both iron and polyunsaturated fatty acids for their survival. This requirement, however, creates a fundamental biochemical conflict in that iron can catalyze peroxidation of polyunsaturated fatty acids through a self-amplifying chain reaction. This reaction will lead to the accumulation of phospholipids containing peroxidized fatty acyl chains, which eventually cause cell death through ferroptosis by disrupting membrane integrity (Fig. 1). Our cells are well aware of this vulnerability, and they develop multiple strategies to guard against ferroptosis (Fig. 1). However, under certain stress conditions, these defenses could fail, leading to tissue damage caused by ferroptosis. Nevertheless, owing to the lack of a biomarker to detect ferroptotic cells under physiological conditions, the exact diseases caused by ferroptosis have been difficult to identify.

We recently addressed this challenge by identifying hyperoxidized PRDX3 as a marker for ferroptosis. In healthy cells, PRDX3 is a mitochondrial peroxiredoxin using its active site cysteine to reduce peroxides including lipid peroxides. Under ferroptotic stress, the accumulation of lipid peroxides in mitochondria triggers hyperoxidation of PRDX3, a reaction converting the active site cysteine thiol to sulfinic or sulfonic acid (Fig. 2A). Importantly, hyperoxidized PRDX3 is robustly induced only by ferroptosis but not other cell death pathways or mitochondrial damage unrelated to ferroptosis, supporting the application of hyperoxidized PRDX3 as a ferroptosis marker.

The identification of this ferroptosis marker allowed us to determine that alcoholic liver disease (ALD) caused liver damage primarily through ferroptosis (Fig. 2B). ALD, one of the most prevalent chronic liver diseases, encompasses a spectrum of disorders including advanced ALD associated with high mortality without effective treatment. My lab is currently interested in understanding how overconsumption of alcohol causes ferroptosis of liver cells so novel treatments of advanced ALD could be developed by strategies that inhibit ferroptosis. Our recent development of a mouse model of advanced ALD, as well as the establishment of cell-based analysis to study cell biology and biochemistry of ferroptosis, has made it possible to pursue these investigations.

Fig. 1. Phospholipid peroxidation triggers ferroptosis

Lipid peroxidation proceeds through three stages. During initiation, Fe2+ reacts with lipid hydroperoxides (LOOH) produced by oxidoreductases such as POR and CYB5R1via Fenton chemistry to generate hydroxyl (•OH) and alkoxyl (LO•) radicals. In the propagation phase, LO• abstracts bis-allylic hydrogen atoms from PUFA-containing PLs (PUFA-PLs), generating PL radicals (PL•), which react with oxygen to form peroxyl radicals (PLOO•). The PLOO• produced attack neighboring PUFA-PLs to generate more PL•, thereby establishing a self-amplifying chain reaction that leads to accumulation of PL hydroperoxides (PLOOH). Lipid-soluble antioxidants terminate PL peroxidation by neutralizing PLOO•. GPX4, an enzyme critical for protection against ferroptosis, detoxifies PLOOH by reducing PLOOH to PL alcohols (PLOH). When the rate of lipid peroxidation exceeds this detoxification capacity, excess PLOOH compromises membrane integrity thus triggering ferroptosis.

 

Fig. 2. The presence of ferroptotic cells in livers with ALD through detection hyperoxidized PRDX3, the ferroptosis marker

  • A. In healthy cells, PRDX3 uses a catalytic Cys thiol (Cp) to reduce peroxides. The Cys sulfenic acid (Cys-SOH) produced by the reaction leads to formation of a disulfide-linked homodimer, and the reduction of which allows the enzymes to continue their catalytic cycle (reactions 1-3). Upon accumulation of excess lipid peroxides in ferroptotic cells, the rate of disulfide bond formation is not fast enough to prevent the Cys-SOH in PRDX3 from further oxidation by the peroxides to generate Cys sulfinic (Cys-SO2H) and sulfonic acid (Cys-SO3H), the hyperoxidation products of PRDX3 (reactions 4 and 5).
  • B. Detection of ferroptotic cells in mouse livers with ALD through immunohistochemistry with an antibody that recognizes hyperoxidized PRDX3.

Meet the PI & Lab Members

Jin Ye, Ph.D.

Jin Ye received a M.S. degree in Biochemistry from Case Western Reserve University in 1995. He was mentored by Nobel laureates Michael Brown and Joseph Goldstein at UT Southwestern, obtaining his Ph.D. in Cell Regulation in 2000, and continuing in a postdoctoral fellowship from 2000 to 2004.He joined the faculty at the UT Southwestern Medical Center in 2004 as an Assistant Professor. He was promoted to Professor in 2022.

Dr. Ye’s research interests are to understand mechanism of diseases caused by abnormal lipid metabolism. Currently his lab is investigating how ferroptosis, a cell death pathway caused by iron-catalyzed peroxidation of polyunsaturated fatty acids, in development of human diseases such as alcoholic liver disease. His lab has employed multiple approaches ranging from in vitro biochemical assays to mouse models of the human diseases to development novel treatments of diseases caused by ferroptosis.

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Yanchao Xu

Senior Research Scientist

Kosuke Kamemura

Postdoctoral Researcher

Lori Nguyen

Research Associate

Publications

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Phone: 214-648-3461

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Department of Molecular Genetics
UT Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75390-9046

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