Author ORCID Identifier
0000-0001-6387-5910
Date of Graduation
8-2024
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Hyun-Eui Kim, Ph.D.
Committee Member
Jian Hu, Ph.D.
Committee Member
Jeff Frost, Ph.D.
Committee Member
Jeff Chang, Ph.D.
Committee Member
Haoqiang Ying, MD, Ph.D.
Abstract
Maintaining protein homeostasis is essential for cellular health. During times of protein stress, cells deploy unique defense mechanisms to achieve resolution. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response (MCSR), a unique stress response activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2a signaling pathway, increasing phosphorylation of eIF2a and improving the ER’s capacity to manage greater proteostasis load. MERSR activation in both poly-glutamine (poly-Q) and amyloid-beta (Aß) C. elegans disease models also leads to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.
Keywords
Mitochondria, ERUPR, Biochemistry, protein homeostasis, ER stress, C. elegans, hsp70