# Mitoribosome protein translation signaling and survival mechanisms

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $727,340

## Abstract

Abstract
Defective mitochondrial function causes cellular damage and death under stress conditions. At the organismal
level mitochondrial dysfunction occurs in mitochondrial diseases caused by genetic mutations,
neurodegeneration, and with less severity during aging, damaging vulnerable tissues such as brain and skeletal
muscle. Mitochondrial mutations cause failures that disrupt energy metabolism, including reductive/oxidative
imbalances and inflammation that lead to tissue damage and eventually death. Mitochondrial defective cells
depend on glycolysis for energy generation and, similar to mitochondrial disease patients, are vulnerable to
stress conditions. The mechanisms that cause this cell damage and how mitochondrial defective cells can be
protected against damage and death are largely unknown. This is important because there are no cures for
mitochondrial diseases, and dysfunctional mitochondria is one of the hallmarks of aging or neurodegeneration.
In genetic and chemical high throughput screens our laboratory has identified a subset of antibiotics, including
tetracyclines, that target the mitoribosome protein translation, and rescue cell death and inflammation in cellular
and mouse models of mitochondrial diseases. Tetracyclines-promoted cell survival depends on suppression of
ER stress and Unfolded Protein Response (UPR) that is independent of the transcription factor ATF4. The
mechanisms of how tetracycline-induced mitoribosome stalling/splitting protect against cell death in cellular and
mouse pre-clinical models of mitochondrial diseases is unknown. We hypothesize that a signaling mechanism
initiated at the stalled/split mitoribosome promotes cell survival in the context of mitochondrial defective cells and
human disease mutations. The main goal of this application is to identify the signaling and cellular
mechanisms caused by stalled and split mitoribosomes that promote cell survival and determine the
efficacy in cellular and mouse models of mitochondrial diseases. We propose 1) to determine the initial
signaling mechanism at the partial stalled/split mitoribosome that promotes survival in mitochondrial disease
mutant cells, focusing on MALSU splitting factor and additional proteins associated at the mitoribosome; 2) to
analyze the components downstream of the stalled/split mitoribosome that promote survival in mitochondrial
disease mutant cells, focusing on components that link the stalled/split mitoribosome to ER stress IRE1a and
UPR responses and 3) to analyze the effects of tetracycline analogs in Ndufs4 KO mice, a mitochondrial complex
I deficient mouse model, focusing on the effects tetracyclines on fitness, survival and modulation of mitoribosome
signaling/ER stress and suppression of brain and skeletal muscle immune inflammation in Ndufs4 KO mice. The
outcomes of this application will determine the regulatory and signaling mechanisms that are initiated by the
stalled/split mitoribosome in conditions of defective mitochondrial...

## Key facts

- **NIH application ID:** 10932874
- **Project number:** 5R01AG086369-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pere Puigserver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $727,340
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932874

## Citation

> US National Institutes of Health, RePORTER application 10932874, Mitoribosome protein translation signaling and survival mechanisms (5R01AG086369-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10932874. Licensed CC0.

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