Apolipoprotein E genotype modulates brain mitovesicle production, a component of mitochondrial quality control - ABSTRACT :
Generation of extracellular vesicles and their release from a cell contributes to cellular waste removal, mediates
the transport of materials between cells, and propagates pathology in the brain. Recently, we characterized a
previously unknown type of extracellular vesicle of mitochondrial origin, the mitovesicle, which we have shown
contains a highly selective compilation of mitochondrial proteins, lipids, RNA, and DNA. Additionally, we have
growing evidence that mitovesicles – their levels, production, and composition – are altered in neurogenerative
diseases and during aging. In several systems where mitophagy is compromised we have shown an increase in
mitovesicles numbers. These findings have led us to propose that mitovesicle secretion supports mitochondria
homeostasis by eliminating detrimental mitochondrial materials from the cell, acting as an important and selective
mitochondrial quality control. Further, when mitophagy is inefficient and mitochondria are stressed, enhanced
mitovesicle production may support cell survival by eliminating oxidized and damaged mitochondrial
components. We have exciting preliminary findings showing that APOE genotype differentially regulates both
brain mitovesicle levels (in the following rank order APOE2>APOE3>APOE4) and their content. Given our
proposed role for mitovesicles as an important mitochondrial quality control, this project will address our
hypothesis that the enhanced release of mitovesicles in APOE2 is beneficial, protecting the cell from
mitochondrial damage, whereas the lower mitovesicle biogenesis in APOE4 is deleterious. Testing whether
APOE genotype and aging modulates mitovesicle levels and content, Aim 1 will elucidate the effects that APOE
genotype has on brain mitovesicles in humanized APOE mice at various ages, with mouse findings confirmed in
human brain tissue. Aim 2 will determine in vitro and in vivo whether mitovesicle production is a protective
component of mitochondrial quality control, one that is enhanced by APOE2 expression and compromised by
APOE4, and whether mitochondrial stress is moderated by robust mitovesicle production. In addition to “waste
removal” mediating mitochondrial health, we have preliminary findings showing that mitovesicles are biologically
active once in the extracellular space, including effects on long-term potentiation (LTP). In Aim 3, we will
determine the impact that brain mitovesicles of differing APOE genotypes and ages have on LTP and
synaptotoxicity, testing the idea that APOE4 causes a “double-hit”, with a reduced number of mitovesicle
compromising mitovesicle-mediated mitochondrial quality control, while the secreted mitovesicles lead to the
transmission of mitovesicle-driven toxicity to other cells. Specifically, this aim will investigate how mitovesicle
content determines the neuronal and synaptic impact of mitovesicles once in the extracellular space, examining
their uptake by target cells, their impact on mitochondria once internalized, and their impact on synapses and
synaptic function. These studies will define the novel role of mitovesicles in mitochondrial homeostasis, a quality
control pathway for mitochondria that we propose is modulated in the brain by APOE genotype.
