# Remodeling mitochondrial cristae to rescue bioenergetic defects in mitochondrial disease

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2021 · $66,390

## Abstract

Project Summary
Mitochondria adapt their shape and influence cellular metabolism in response to the physiological state of
the cell. Cristae are dynamic compartments of the mitochondrion that dictate its bioenergetic capacity by
regulating the kinetics of Oxidative Phosphorylation (OXPHOS) reactions and the structure of the OXPHOS
complexes. Cristae shape is regulated during many pathological conditions, including mitochondrial
diseases with no available cure. Here, the molecular mechanisms that underlie cristae remodeling will be
investigated to rescue bioenergetic defects observed in mitochondrial disorders by combining
ultrastructural, biochemical and bioenergetic analyses.
The Puigserver Lab has shown that a component of the ER stress response, R(PKR)-like ER kinase
(PERK), remodels cristae and mediates an energetic shift to promote mitochondrial respiration through the
elf2α-ATF4 axis. The communication between the ER and mitochondria in the context of cristae formation is
a relatively under-explored area and the regulation of this cross-talk is unclear. This proposal investigates a
novel role for the PERK pathway in rescuing cristae shape during mitochondrial disease. Aim 1 focuses on
the downstream effects of PERK and how the metabolomic and proteomic signatures of mitochondria are
altered to rescue bioenergetic defects seen in OXPHOS Complex I deficient cells. Aim 2 characterizes the
contribution of the ER-mitochondria contact sites to PERK mediated cristae formation. Aim 3 explores
additional kinases like PERK that are known to phosphorylate elf2α in response to different types of stress,
and their potential role in rescuing bioenergetic defects in mitochondrial mutants.
The Puigserver is part of a dynamic research community at the Dana Farber Cancer Institute and Harvard
Medical School, with established tools, cell lines and methodologies to explore mitochondrial metabolism
and perform all the proposed experiments. These studies hope to identify and explore new pathways that
regulate cristae shape to rescue bioenergetic defects associated with mitochondrial disease.

## Key facts

- **NIH application ID:** 10132190
- **Project number:** 5F32GM136019-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Beste Mutlu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132190

## Citation

> US National Institutes of Health, RePORTER application 10132190, Remodeling mitochondrial cristae to rescue bioenergetic defects in mitochondrial disease (5F32GM136019-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132190. Licensed CC0.

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