# Molecular mechanism of Ca2+-induced mitochondrial shape transition in metazoans

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $400,748

## Abstract

PROJECT SUMMARY / ABSTRACT
Ca2+ is a critical second messenger that is required for several cellular processes. Cytosolic Ca2+ (cCa2+)
transients are shaped by the mitochondria due to the highly negative membrane potential and through the
mitochondrial calcium uniporter (MCU). Mitochondrial Ca2+ (mCa2+) is utilized by the matrix dehydrogenases for
maintaining cellular bioenergetics. Reciprocally, dysregulated elevation of cCa2+ under conditions of stroke,
ischemia/reperfusion injury drives mCa2+ overload that in turn leads to mitochondrial permeability transition pore
opening that triggers necrotic cell death. Hence, it was thought that preventing mCa2+ overload can be
protective under conditions of elevated cCa2+. Contrary to this, mice knocked-out for MCU, which demonstrated
no mCa2+ uptake and hence no mitochondrial swelling, surprisingly did not offer any protection from IR
mediated cell death, suggesting that loss of MCU-mediated Ca2+ overload was not sufficient to protect cells
from Ca2+-induced necrosis. To understand the molecular mechanisms of elevated Ca2+-induced cell death, we
performed ultra-structural analysis of liver harvested from liver specific MCU-/- (MCUHEP) and MCUfl/fl animals.
Electron microscopy studies revealed stark contrast in the shape of mitochondria: MCUfl/fl liver sections
showed long and filamentous mitochondria (spaghetti-like) while MCUHEP mitochondria were short and circular
(donut-like). We hypothesized this Mitochondrial Shape Transition phenomenon that we refer hereafter as
MiST, to be cCa2+-induced and independent of mitochondrial swelling or Drp1-mediated mitochondrial fission.
Based on our preliminary results, we hypothesize that pathophysiological elevation of cCa2+ induces MiST and
that is Miro-1 driven. Because cellular mitochondrial networks allow for the sharing of metabolites, proteins,
mitochondrial DNA and potential energy distribution, there is an extensive risk for local mitochondrial failures to
quickly spread over the entire network and compromise cellular energy conversion. Like power networks that
physically segment elements with circuit breakers, we hypothesize that MiST protects mitochondrial networks
from propagating local failures. Our recently completed whole genome-wide CRISPR/Cas9 Library screen in
MEFs identified a conserved protein, S100z to be the cytosolic component for MiST. We expect MiST to be a
sequential step with a major determinant to be the cCa2+ transients and the molecular component to be shared
by the cytosol (S100Z) and the mitochondria (Miro1). We also hypothesize that MiST is likely to be conserved
in metazoans and would facilitate lysosomal removal by autophagy/mitophagy depending on the varying cCa2+
transients, thus preserving the quality of the mitochondrial network. The revelation of this Ca2+-induced
phenomenon and the identification of the molecular components will resolve the spatio-temporal molecular
mechanisms of MiST. Successful accomplishment of our prop...

## Key facts

- **NIH application ID:** 9842628
- **Project number:** 5R01GM109882-06
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** MADESH MUNISWAMY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,748
- **Award type:** 5
- **Project period:** 2014-08-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842628

## Citation

> US National Institutes of Health, RePORTER application 9842628, Molecular mechanism of Ca2+-induced mitochondrial shape transition in metazoans (5R01GM109882-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9842628. Licensed CC0.

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