Bio

Research & Scholarship

Current Research and Scholarly Interests


I am interested in the molecular mechanisms that regulate mitochondrial dynamics. I am using rationally-designed peptide inhibitors to target mitochondrial fission/fusion factors in order to understand the interplay between these factors under normal and stressed cellular conditions.

Lab Affiliations


Publications

All Publications


  • The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained. Cell calcium Joshi, A. U., Kornfeld, O. S., Mochly-Rosen, D. 2016; 60 (3): 218-234

    Abstract

    Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca(2+) transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases.

    View details for DOI 10.1016/j.ceca.2016.04.010

    View details for PubMedID 27212603

  • Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation. Journal of visualized experiments : JoVE Qvit, N., Kornfeld, O. S. 2016

    Abstract

    Protein-protein interactions (PPIs) are intimately involved in almost all biological processes and are linked to many human diseases. Therefore, there is a major effort to target PPIs in basic research and in the pharmaceutical industry. Protein-protein interfaces are usually large, flat, and often lack pockets, complicating the discovery of small molecules that target such sites. Alternative targeting approaches using antibodies have limitations due to poor oral bioavailability, low cell-permeability, and production inefficiency. Using peptides to target PPI interfaces has several advantages. Peptides have higher conformational flexibility, increased selectivity, and are generally inexpensive. However, peptides have their own limitations including poor stability and inefficiency crossing cell membranes. To overcome such limitations, peptide cyclization can be performed. Cyclization has been demonstrated to improve peptide selectivity, metabolic stability, and bioavailability. However, predicting the bioactive conformation of a cyclic peptide is not trivial. To overcome this challenge, one attractive approach it to screen a focused library to screen in which all backbone cyclic peptides have the same primary sequence, but differ in parameters that influence their conformation, such as ring size and position. We describe a detailed protocol for synthesizing a library of backbone cyclic peptides targeting specific parasite PPIs. Using a rational design approach, we developed peptides derived from the scaffold protein Leishmania receptor for activated C-kinase (LACK). We hypothesized that sequences in LACK that are conserved in parasites, but not in the mammalian host homolog, may represent interaction sites for proteins that are critical for the parasites' viability. The cyclic peptides were synthesized using microwave irradiation to reduce reaction times and increase efficiency. Developing a library of backbone cyclic peptides with different ring sizes facilitates a systematic screen for the most biological active conformation. This method provides a general, fast, and facile way to synthesize cyclic peptides.

    View details for DOI 10.3791/53589

    View details for PubMedID 26863382

  • Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature Franco, A., Kitsis, R. N., Fleischer, J. A., Gavathiotis, E., Kornfeld, O. S., Gong, G., Biris, N., Benz, A., Qvit, N., Donnelly, S. K., Chen, Y., Mennerick, S., Hodgson, L., Mochly-Rosen, D., Dorn, G. W. 2016

    Abstract

    Mitochondria are dynamic organelles, remodeling and exchanging contents during cyclic fusion and fission. Genetic mutations of mitofusin (Mfn) 2 interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition, Charcot Marie Tooth disease type 2A (CMT2A). It has not been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is incompletely understood. Here we show that mitofusins adopt either a fusion-constrained or fusion-permissive molecular conformation directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated by targeting these conformational transitions. Based on this model we engineered a cell-permeant minipeptide to destabilize fusion-constrained mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons harboring CMT2A gene defects. The relationship between mitofusin conformational plasticity and mitochondrial dynamism uncovers a central mechanism regulating mitochondrial fusion whose manipulation can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics.

    View details for DOI 10.1038/nature20156

    View details for PubMedID 27775718

  • Mitochondrial reactive oxygen species at the heart of the matter: new therapeutic approaches for cardiovascular diseases. Circulation research Kornfeld, O. S., Hwang, S., Disatnik, M., Chen, C., Qvit, N., Mochly-Rosen, D. 2015; 116 (11): 1783-1799

    Abstract

    Reactive oxygen species (ROS) have been implicated in a variety of age-related diseases, including multiple cardiovascular disorders. However, translation of ROS scavengers (antioxidants) into the clinic has not been successful. These antioxidants grossly reduce total levels of cellular ROS including ROS that participate in physiological signaling. In this review, we challenge the traditional antioxidant therapeutic approach that targets ROS directly with novel approaches that improve mitochondrial functions to more effectively treat cardiovascular diseases.

    View details for DOI 10.1161/CIRCRESAHA.116.305432

    View details for PubMedID 25999419

  • Mitochondrial Reactive Oxygen Species at the Heart of the Matter New Therapeutic Approaches for Cardiovascular Diseases CIRCULATION RESEARCH Kornfeld, O. S., Hwang, S., Disatnik, M., Chen, C., Qvit, N., Mochly-Rosen, D. 2015; 116 (11): 1783-1799