Project Summary/Abstract
The candidate for this award seeks further mentored research experience while developing career skills to
facilitate a successful transition to research independence. Therefore, she has proposed additional
experimental and professional training during her postdoctoral fellowship in the lab of Dr. Toren Finkel at the
NHLBI. She will take advantage of the outstanding scientific environment in her mentor's lab and at the NHLBI
to learn new techniques, including proteomics, RNA sequencing, bioinformatics and computational analysis,
and animal work including advanced phenotyping tests. To train her in these methods and assist her in her
research aims, she has established collaborations with Dr. Elizabeth Murphy's lab and several NHLBI core
facilities. Furthermore, the candidate has designed a career development plan to ensure she prepares
thoroughly for an academic position by cultivating her oral and written communication, mentorship, and lab
management skills. The candidate has assembled an advisory committee consisting of her primary mentor and
several other scientists who not only have extensive scientific experience in fields related to the mitochondrial
biology proposed in this grant, but also have committed to guiding her on presentations, job applications, and
negotiation strategies. This training will help the candidate secure a tenure-track position in academia.
The research goal of this proposal is to dissect the molecular mechanism and physiological role of
mitochondrial calcium regulation. Mitochondrial uptake of calcium can help to stimulate ATP production, but too
much calcium can lead to opening of the mitochondrial permeability transition pore, triggering cell death. The
selective channel through which calcium can rapidly enter the mitochondria, the mitochondrial calcium
uniporter, is a multi-protein complex whose components are beginning to be identified. EMRE and MICU1 are
two of these proteins that in cell lines have been shown to play critical roles in regulation of calcium uptake.
The candidate has generated the first mouse models of EMRE and MICU1 deletion to elucidate the in vivo role
of mitochondrial calcium. Her recent publication showed that MICU1 deletion leads to mitochondrial calcium
overload, leading to drastically decreased survival and other defects. She will next characterize the effect of
EMRE deletion on the molecular architecture of the uniporter as well as on organismal physiology (Aim 1). Her
preliminary data suggest that without EMRE, mitochondria cannot uptake calcium. Therefore, the candidate will
use MICU1 and EMRE deletion as genetic reagents representing “gain” and “loss” of function in terms of
mitochondrial calcium uptake to elucidate how mitochondrial calcium regulation alters in vivo physiological
function in global gene expression, aging, and disease (Aim 2). A number of muscular and neurodegenerative
diseases have long been associated with mitochondrial calcium overload, but the generation of these mouse
models will enable the first direct tests of the impact of mitochondrial calcium on organismal physiology. The
completion of these aims thus is of both basic and clinical importance.