B.A. (Cum Laude), Agriculture, Hebrew University of Jerusalem
M.Sc., Botany, Hebrew University of Jerusalem
Ph.D., Rutgers University, NJ
My research interests are focused on the role Reactive Oxygen Species (ROS) play in the regulation of different biological processes. As model organisms I use Arabidopsis thaliana plants and human epithelial breast cancer cells because they provide an ideal platform for the questions I am interested in. My approach to research is to focus on questions that are biologically important (and fundable), and to address them using a comprehensive approach of molecular genetics, biochemistry, structural biology, physiology, biophysics, chemistry, bioinformatics, omics and systems biology. I strive to obtain a deep understanding of the biological process in question by making predictions, generating models, and integrating data from different platforms, as well as by using different mutants and imaging tools to test my hypotheses. I collaborate with different computational biologists (e.g., Jose’ Onuchic), bioinformaticians (e.g., Rajeev Azad), and biostatisticians (e.g., Karen Schlauch), as well as with different plant physiology (e.g., Eduardo Blumwald) and cancer (e.g., Eli Pikarski) experts, and chemists (e.g., Itamar Willner). To me, the ultimate reward in science is to find out how all the pieces of the scientific puzzle fit together to provide an answer to the working hypothesis (or change it if not…). Some of the important contributions I made so far include the discovery of the ROS wave and the important role it plays in systemic responses in plants, the establishment of the abiotic stress combination research field in plants and the different findings I made regarding the response of plants to a combination of two different stresses, and the definition of the ROS gene network of Arabidopsis that was followed by the characterization of different mutants involved in this network. In recent years I have also begun to address the common pathways and genes that regulate ROS and iron metabolism in plant and animal cells, and to focus on rapid responses at the transcriptome and metabolome level that accompany abiotic stress responses. One of the most interesting findings that emerged from these studies was the discovery that the 2Fe-2S protein NAF-1 plays a key role in regulating cellular proliferation and tolerance to oxidative stress in human epithelial breast cancer cells and tumors. Below I outline the three main projects underway in my laboratory.
1. The ROS Wave and Ultrafast Omics Responses to Abiotic Stress
Systemic signaling pathways enable multicellular organisms to prepare all of their tissues and cells to an upcoming challenge that may initially only be sensed by a few local cells. They are activated in plants in response to different stimuli including mechanical injury, pathogen infection, and abiotic stresses. Key to the mobilization of systemic signals in higher plants are cell-to-cell communication events that have thus far been mostly unstudied. My recent discovery of systemically propagating reactive oxygen species (ROS) waves in plants has unraveled a new and exciting cell-to-cell communication pathway that, together with calcium and electric signals, could provide a working model to how plant cells transmit long-distance signals via cell-to-cell communication mechanisms. My study of rapid systemic signaling has also focused my attention on rapid local responses to stress and on the cross talk between ROS, ABA and stomatal responses. These have brought me to formulate another hypothesis on plant systemic responses called the leaf autonomous response pathway. Supported by IOS-1353886 and IOS-1063287.
Miller G, Schlauch K, Tam R, Cortes D, Torres MA,, Shulaev V, Dangl JL, Mittler R (2009) The plant NADPH oxidase RbohD mediates rapid, systemic signaling in response to diverse stimuli. Science Signaling.18;2(84):ra45.
Mittler R, Vanderauwera S, Suzuki N, Miller G, Tognetti VB, Vandepoele K, Gollery G, Shulaev V, Van Breusegem F (2011) ROS signaling: The new wave? Trends Plant Sci. 16(6):300-9.
Suzuki N, Miller G, Salazar C, Mondal HA, Shulaev E, Cortes DF, Shuman JL, Luo X, Shah J, Schlauch K, Shulaev V, Mittler R. (2013). Temporal-spatial interaction between ROS and ABA controls rapid systemic acclimation in plants. Plant Cell. 25(9):3553-69.
Gilroy S, Suzuki N, Miller G, Choi WG, Toyota M, Devireddy AR, Mittler R. (2014) A tidal wave of signals: calcium and ROS at the forefront of rapid systemic signaling. Trends Plant Sci. 19(10):623-630.
Mittler R, Blumwald E. (2015) The Roles of ROS and ABA in Systemic Acquired Acclimation. Plant Cell. 27(1):64-70.
Suzuki N, Devireddy AR, Inupakutika MA, Baxter A, Miller G, Song L, Shulaev E, Azad RK, Shulaev V, Mittler R. (2015) Ultra-fast alterations in mRNA levels uncover multiple players in light stress acclimation in plants. Plant J. 84(4):760-72.
Devireddy AR, Zandalinas SI, Gómez-Cadenas A, Blumwald E, Mittler R (2018) Coordinating the overall stomatal response of plants: Rapid leaf-to-leaf communication during light stress. Science Signaling, Feb 20;11(518).
2. Stress Combination
Abiotic stress is the primary cause of crop loss worldwide, with losses in the US estimated at 14-19 billion dollars each year. While abiotic stress is routinely studied in plants by applying a single stress condition such as drought, salinity or heat, this type of analysis does not reflect the conditions that occur in the field or in nature in which crops and plants are subjected to a combination of different stresses (e.g., drought and heat). Because abiotic stress combinations had the outmost devastating economical and sociological impacts on the US, with losses of 48.4 and 61.6 billion dollars in 1980 and 1988 respectively, and because these extreme weather events are likely to increase in frequency due to global warming, the development of transgenic crops with improved tolerance to abiotic stress combinations is a highly important goal that would provide a promising avenue to reduce yield losses and secure food supply for our growing population. My initial studies into abiotic stress combinations in plants demonstrated that the response of plants to a combination of two different stresses is unique and cannot be directly extrapolated from the response of plants to each of the different stresses applied individually. I have also identified several key regulatory proteins required for the acclimation of plants to stress combinations. I am currently working towards the identification of important regulatory networks that mediate the acclimation of plants to abiotic stress combinations, as well as towards the development of plants and crops with enhanced tolerance to stress combination. Supported by IOS-0820188.
Rizhsky L., Liang H., Shuman J., Shulaev V., Davletova S. and Mittler R. (2004) When defense pathways collide: The response of Arabidopsis to a combination of drought and heat stress. Plant Physiol. 134, 1683-1696.
Mittler. R (2006) Abiotic Stress, the Field Environment and Stress Combination. Trends Plant Sci. 11, 15- 19.
Mittler R, Blumwald E (2010) Genetic engineering for modern agriculture: Challenges and perspectives. Ann. Rev. Plant Biol. 61:443-62.
Suzuki N, Sejima H, Tam R, Schlauch K, Mittler R (2011) Identification of the MBF1 heat-response regulon of Arabidopsis thaliana. Plant J. 66(5):844-51.
Suzuki N, Miller G, Sejima H, Harper J, Mittler R. (2013) Enhanced seed production under prolonged heat stress conditions in Arabidopsis thaliana plants deficient in cytosolic ascorbate peroxidase 2. J Exp Bot. 64(1):253-63.
Suzuki N, Rivero RM, Shulaev V, Blumwald E, Mittler R. (2014) Abiotic and biotic stress combinations. New Phytol. 203(1):32-43.
Suzuki N, Basil E, Hamilton JS, Inupakutika MA, Tripathy D, Luo Y, Dion E, Fukui G, Kumazaki A, Nakano R, Rivero RM, Verbeck GF, Azad RK, Blumwald E, Mittler R. (2016) ABA is Required for Plant Acclimation to a Combination of Salt and Heat Stress. PLoS One. 11(1):e0147625.
Zandalinas SI, Arbona V, Gómez-CadenasA, Inupakutika MA, Mittler R. (2016) ABA is required for the accumulation of APX1 and MBF1c during a combination of water deficit and heat stress J. Exp Bot. 67(18):5381-5390.
3. Regulation of Cell Survival and Death Pathways by Fe-S Proteins
Maintaining iron and reactive oxygen species (ROS) homeostasis is essential for cellular proliferation, stress responses, and the regulation of cell survival and death pathways in plant and animal cells. The recent discovery of a novel group of Fe-S containing proteins with a redox-sensitive labile 2Fe-2S cluster in plant and animal cells (NEET proteins), provides one of the first links between the regulation of iron levels and ROS homeostasis in cells. Our studies show that the function of NEET proteins is both ancient and essential for proper iron/ROS/Fe-S mobilization in cells. We propose that NEET proteins use their redox-active labile clusters to sense the levels of ROS/redox in cells, and depending on these levels they either promote cellular proliferation, or trigger the activation of apoptosis and autophagy. We recently discovered that the degree of lability of the NEET’s 2Fe-2S clusters and their overall protein levels in cells are crucial for making this decision, and have shown using different mutants and other molecular tools that cancer cells that accumulate high levels of wild type NEET proteins (but not mutant NEET proteins with a high cluster stability) are protected from oxidative stress and can proliferate faster. Our findings establish a key role for NEET protein overexpression in promoting the tumorigenicity of breast cancer cells. Furthermore, they provide a mechanistic foundation for the role of NEET overexpression in multiple cancer types, including breast, prostate, gastric, cervical, liver, and laryngeal cancers. We are currently working toward developing different therapies (drugs, peptides), as well as different delivery methods (nanoparticles) that will target the stability of the 2Fe-2S cluster of NEET proteins, thereby alter the redox/ROS levels of cells. These would be applicable not only for the treatment of different cancers that rely on high expression levels of NEET proteins for their proliferation, but also for the treatment of diabetes and certain neurodegenerative diseases that have also been linked to NEET protein overexpression. Supported by MCB-1613462 and IOS-1557787; proposals pending with NIH.
Nechushta R, Conlan A, Song L, Harir Y, Yogev O, Eisenberg-Domovich Y, Livnah O, Michaeli D, Rosen R, Ma V, Luo Y, Zuris JA, Shulaev V, Paddock ML, Cabantchik I, Jennings PA, Mittler R (2012) Arabidopsis thaliana ChloroNEET, a Member of the New NEET Family of Human Proteins, is Involved in Development, Senescence and Iron Metabolism. Plant Cell. 24:2139-2154
Sohn YS, Tamir S, Song L, Michaeli D, Matouk I, Conlan AR, Harir Y, Holt SH, Shulaev V, Paddock ML, Hochberg A, Cabanchick IZ, Onuchic JN, Jennings PA, Nechushtai R, Mittler R. (2013) NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci U S A. 110(36):14676-81.
Holt SH, Darash–Yahana M, Sohn YS, Song L, Karmi O, Tamir S, Michaeli D, Luo Y, Paddockc ML, Jennings PA, Onuchic JN, Azad RK, Pikarsky E, Cabantchik IZ, Nechushtai R, Mittler R. (2015) Activation of Apoptosis in NAF-1-Deficient Human Epithelial Breast Cancer Cells. J Cell Sci. 129(1):155-65.
Danielpur L, Sohn Y-S, Karmi O, Fogel C, Zinger A, Abu-Libdeh A, Israeli T, Riahi R, Pappo O, Birk R, Zangen DH, Mittler R, Cabantchik ZI, Cerasi E, Nechushtai R, Leibowitz G. (2016) GLP-1-RA corrects mitochondrial labile iron accumulation and improves beta-cell function in type 2 Wolfram syndrome. J. Clinical Endocrinology & Metabolism. 101(10):3592-3599.
Darash-Yahanaa M, Pozniakb Y, Luc M, Sohn Y-S, Karmi O, Tamir S, Bai F, Song L, Jennings PA, Pikarsky E, Geiger T, Onuchic JN, Mittler R, Nechushtai R. (2016) Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters. Proc Natl Acad Sci U S A. 113(39):10890-5.
King SD, Gray CF, Song L, Nechushtai R, Gumienny TL, Mittler R, Padilla PA (2017) The cisd gene family regulates physiological germline apoptosis through ced-13 and the canonical cell death pathway in Caenorhabditis elegans. Cell Death & Differentiation. In press.