# Structure, function, and disease biology of MICU1/MICU2

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $450,340

## Abstract

ABSTRACT
Mitochondria uptake calcium via a calcium activated channel called the uniporter. Calcium uptake allows the
organelle's metabolic state to be matched to rapidly changing energy requirements, and, in turn, tune
key processes such as neurotransmission and muscle contraction. The uniporter is calcium-activated calcium
channel regulated by the calcium binding heterodimer MICU1/MICU2. Mutations in MICU1 have recently been
identified as a cause of a new form of a myopathy characterized by fatigue and exercise intolerance without
the classical features of mitochondrial myopathy. The precise mechanisms by which MICU1 and MICU2 sense
calcium to regulate the uniporter, and how lesions in this heterodimer lead to this highly unusual myopathy are
not known. Through this dual PI grant we propose to: (1) Characterize the physicochemical properties of
MICU1 and MICU2. The wild type proteins and mutants expressed in E. coli will be characterized with respect
to the oligomeric state, structural stability, Ca2+ and Mg2+ binding affinities, and pH sensitivity. (2) Determine the
structural basis for the regulation of the uniporter by MICU1 and MICU2. High resolution X-ray structures of
MICU2 alone and of the MICU1/2 heterodimer in the apo and Ca2+-bound forms will be determined.
Electron cryo-microscopy will be used to determine the structure of a native-like oligomer of MICU1/2
complex. (3) Investigate mitochondrial calcium dynamics in cellular systems. Using genome-editing technology
we have engineered a powerful in vivo system of knockout cell lines for studying the effects of engineered and
naturally occurring human mutations in MICU1 and MICU2 on the mitochondrial calcium transport kinetics and
energetics, and (4) Understand the metabolic and bioenergetic basis of human MICU1 myopathy by
investigating the Micu1-/- mouse as a model. We will characterize the muscle histology, mitochondrial
bioenergetics, exercise performance and metabolomics, and single fiber contractility to test the hypothesis that
loss of MICU1 leads to a myopathy by causing disturbances in energy metabolism. Our aims – spanning the
molecular to animal physiology -- will yield a holistic and mechanistic understanding of the regulation
of mitochondrial calcium uptake by MICU1 and MICU2 and its contribution to a newly described human
myopathy.

## Key facts

- **NIH application ID:** 10197754
- **Project number:** 5R01AR071942-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zenon Grabarek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,340
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197754

## Citation

> US National Institutes of Health, RePORTER application 10197754, Structure, function, and disease biology of MICU1/MICU2 (5R01AR071942-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197754. Licensed CC0.

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