# Pathogensis of myopathies caused by novel mitochondrial phosphate carrier mutations

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $300,300

## Abstract

The mitochondrial phosphate carrier (PiC), encoded by the nuclear gene SLC25A3, was purified more than 30
years ago. It has been long believed that PiC serves as the primary means of phosphate (Pi) uptake into
mitochondria for oxidative phosphorylation (oxphos) and as the main buffering species for the vast amount of
calcium that mitochondria can take up. However, only very recently have mutations in human PiC been
discovered, and a PiC floxed mouse has been generated, allowing PiC function to be directly studied in vivo for
the first time. Human PiC mutations result in a severe clinical phenotype, with onset soon after birth and
striated muscle as a key affected tissue. Similarly, mice with cardiac-specific deletion of the PiC had abnormal
cardiac function; however, the extent to which this was caused by a defect in oxphos, dysregulated Ca2+
signaling related to poor mitochondrial Ca2+ buffering, and/or to matrix swelling caused by mitochondrial Ca2+
uptake in the absence of Pi uptake is unknown. Yet, these are fundamental questions about a basic process,
namely mitochondrial Pi uptake that supports energy production and Ca2+ homeostasis. Here we hypothesize
that perturbation of PiC in skeletal muscle causes a bioenergetic and Ca2+ handling deficit that worsens when
energy demand rises. Because fusion of the inner mitochondrial membrane requires mitochondrial ATP, we
further hypothesize that the bioenergetics deficit will lead to impaired mitochondrial fusion-fission dynamics.
These hypotheses will be tested using new genetic models: mice with skeletal muscle-specific PiC depletion,
and myotubes and fibroblasts from PiC deficient individuals with natural SLC25A3 mutations. Aim 1 will test
the dependence on PiC of mitochondrial Pi uptake and oxidative phosphorylation, and will also consider
whether alternate transport mechanisms counter PiC deficiency. We will also investigate how PiC deficient
skeletal muscle responds to PiC deficiency in terms altered glycolytic flux and nutrient signaling, exercise
tolerance and mechanical function. Aim 2 will test if PiC deficiency causes dysregulation of cytoplasmic and
mitochondrial Ca2+, and Ca2+ regulated functions. Pi uptake is required for effective mitochondrial Ca2+
handling and a Ca2+ rise triggers each muscle contraction. Dysregulation of mitochondrial Ca2+ is also a main
trigger of mitochondrial restructuring and cell death. Thus it is imperative to determine the consequence of PiC
deficiency in terms of Ca2+ homeostasis. From preliminary results we hypothesize that PiC deficiency impairs
mitochondrial Ca2+ handling, leading to cytoplasmic Ca2+ dysregulation, mitochondrial fragmentation,
membrane permeabilization and cell death. To test this hypothesis, multiparameter Ca2+ and functional assays
will be carried out in the genetic models presented by the mice and the patient cells. Studies from both Aims
will help to delineate 1) the extent of PiC's biological functions in skeletal muscle, 2) the (ma...

## Key facts

- **NIH application ID:** 9990803
- **Project number:** 5R01GM123771-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Erin Seifert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,300
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990803

## Citation

> US National Institutes of Health, RePORTER application 9990803, Pathogensis of myopathies caused by novel mitochondrial phosphate carrier mutations (5R01GM123771-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9990803. Licensed CC0.

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