Mitochondria-induced Bioenergetic Independent Stress Signaling in the Heart

Abstract

Mitochondria are well known for their function in providing energy supply to the cell. Aside from these "bioenergetic" functions, mitochondria perform many other essential processes. To accomplish these functions, mitochondria must import many proteins from the cytosol. This import process can sometimes become dysfunctional and induce a severe stress on the cell via the mistargeting of mitochondrial proteins to the cytosol. Our lab termed this specific type of cell stress as mitochondrial precursor overaccumulation stress (mPOS). Our work has focused on demonstrating that mPOS is able to occur in various models of disease, both in vivo and in vitro. In this thesis we demonstrate that mPOS can occur in the heart of mice and induce significant signaling and functional changes over the lifespan (chapter 2). Additionally, in a related work, we found that mitochondrial protein import clogging can induce mPOS in the central nervous system (CNS) and potentiate pathology in a mouse model of Parkinson's disease (appendix I). Most importantly, all the changes occurring in both animal models do not necessarily co-occur with bioenergetic deficiencies. The implication of this is that mPOS may be a bioenergetic independent mechanism liking mitochondrial dysfunction with tissue dysfunction. Speaking more generally, mPOS may occur in many clinically relevant conditions such as heart failure, normative ageing, muscle loss, and neurodegenerative diseases. This work and future work therefore aims to establish the basic mechanisms by which mPOS may occur within cells and how cells can in turn respond to this stress.