Regulation of Mitochondrial Functions by Iron and Ceramides in C. elegans

University Of North Texas, Denton TX

Investigators

Abstract

Biological processes such as responses to stress, cell death and lifespan depend on maintaining a balance among levels of various compounds such as fats (lipids), iron and sugars. Although substantial research efforts have revealed how the levels of fats and sugars are controlled by different hormones, such as insulin, the connection of these processes to processes that regulate iron levels is poorly understood. Recently, the investigators identified cellular processes that potentially integrate the ways that iron and lipid levels are maintained. The investigators will determine the dynamics and interaction between iron homeostasis and synthesis of specific lipids (ceramides), and how these interactions impact organismal functions such as metabolism, cell death and responses to stress. A genetic model system will be used to identify novel genes involved with cellular iron and lipid homeostasis. Additionally, the investigators will incorporate their research with education by providing research opportunities and mentoring to graduate and undergraduate students. Furthermore, an outreach-based learning module will be incorporated into the existing and successful UNT Elm Fork Education Center. This science education center reaches over 20,000 visitors per year (majority are K-8th graders). By collaborating with the Elm Fork Education Center students will be exposed to the field of genetic modeling and the cellular responses to environmental stress in animals. Completion of this project will elucidate novel mechanisms regulating mitochondrial function relative to whole animal biology. The goals of this project are to dissect the pathways controlling sphingolipid/ceramide metabolism and iron regulation and to determine if sphingolipid/ceramide metabolism and iron regulation are mechanistically linked. The approach is to use the genetic model system Caenorhabditis elegans to conduct cellular, molecular and genetic analysis on mutants with altered sphingolipid/ceramide metabolism and iron regulation. The investigators will test the hypothesis that 1) central features of mitochondrial function and the response to oxygen deprivation in an intact whole organism are sphingolipid/ceramide metabolism and iron regulation; and 2) sphingolipid/ceramide metabolism and iron regulation are mechanistically linked in mitochondrial functions. To test these hypothesis the following Specific Aims will be conducted: Aim 1: Determine how ceramide biosynthesis and iron regulation impact mitochondria functions and whole organism stress responses; Aim 2: Conduct genetic suppression analyses to identify signaling pathways that interact with ceramide biosynthesis and iron regulation; Aim 3. Utilize genetic analysis to determine if neet-1 and ceramide biosynthesis mechanistically interact to regulate mitochondrial functions. The proposed research could have a transformative impact on the way sphingolipid/ceramide metabolism and iron regulation is viewed in the context of mitochondrial homeostasis. The project provides research training for graduate and undergraduate students. Furthermore, an outreach-based learning module that focuses on the genetic model system C. elegans will be offered through a program at the UNT Elm Fork Education center. This outreach program will have a broad impact since it reaches over 20,000 visitors per year.