Suzanne Angeli

Biography: Dr. Angeli, Assistant Professor of Molecular & Cellular Biology

COBRE pilot project: The Impact of Extracellular Calcium Signalling on the Mitochondria Unfolded Protein Response

Abstract

Inter-tissue communication underpins the coordination and regulation of complex physiological processes throughout the body. Reproductive tissues influence a vast number of physiological processes through hormonal, cellular, and systemic pathways. The impact of reproductive tissues on distal tissues can be both protective and detrimental depending on context, and studying this interplay helps us understand mechanisms of aging and disease. This is especially significant for women since decades of male-biased research have excluded female research subjects, which has left a palpable hole in our knowledge of how pregnancy and reproduction may alter the aging and disease process in women. This proposed research will begin to unravel the complex pathways associated with germline-to-soma signaling and specifically inform us on how tissue-specific Ca2+ signaling during reproduction impacts somatic mitochondrial health. The use of the simple nematode C. elegans has been a linchpin in elucidating inter-tissue communication, especially inter-tissue mitochondrial communication, a central player in health and disease. The mitochondrial unfolded protein response (UPRmt) is a fundamental transcriptional response that aids in the repair and refolding of mitochondrial matrix proteins, which is essential for maintaining mitochondrial health and integrity. In C. elegans, UPRmt activation is largely localized to the intestines, which, in addition to digestion, also carries out many functions similar to the liver, such as detoxification, immunity, and fat metabolism 2. We have identified that calmodulin (CaM), a cytosolic and nuclear Ca2+ signaling protein, is essential for the activation of the intestinal UPRmt in C. elegans (unpublished data). Additionally, we have identified that the germline tissue is essential for the intestinal UPRmt. Specifically, our preliminary data suggests that fertilization, a Ca2+-demanding process, is essential for intestinal UPRmt activation. We hypothesize that Ca2+ signals from fertilization in the germline lead to an upregulation of intestinal Ca2+ levels and receptivity to intestinal UPRmt activation (Figure 1). Here, we present two complementary aims that will help us decipher the role of germline Ca2+ signaling on intestinal Ca2+ levels and UPRmt activation. Aim 1 will determine whether germline Ca2+ signaling via CaM is essential for intestinal UPRmt activation by using mutant C. elegans that express germline-specific RNA interference (RNAi) sensitivity. Aim 2 will determine whether fertilization leads to an increase in intestinal Ca2+ levels and receptivity to intestinal UPRmt activation by comparing wild-type and fertilization-deficient C. elegans. To measure Ca2+ levels in the intestines, we will use sophisticated microscopy tools via the COBRE Microscopy and Image Analysis Core. The results from these studies will provide fundamental insights into inter-tissue mitochondrial communication via Ca2+, which has broad implications for human health.