# Coordination of PAR and Ub signaling in mitochondria

> **NIH NIH R35** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $439,725

## Abstract

Project Summary/Abstract
Over the past 10 years, our research program has aimed at discovering molecular mechanisms that control
metabolic adaptation in response to nutrient availability, cellular differentiation, and oxidative stress through
genomic reprogramming. With NIGMS support, we have made significant contributions to identifying
mechanisms responsible for the coordinated regulation of gene transcription and translation during the
Mitochondrial Stress Response (MSR). Our work has identified a key role for non-degradative ubiquitination in
both processes, showing that the regulated shuttling of GPS2 – an endogenous inhibitor of K63 ubiquitination –
between mitochondria and nucleus is an essential strategy for maintaining mitochondrial homeostasis. As a
complement to these mechanistic studies, we also investigated – in projects supported by NIDDK and the
Department of Defense – the physiological relevance and translational potential GPS2-mediated regulation of
ubiquitin signaling in breast cancer and obesity-associated disorders. Together, these studies have revealed the
importance of GPS2-mediated restriction of K63Ub signaling in promoting metabolic adaptation and
mitochondria remodeling during stress and cellular differentiation. This large body of work highlights our
expertise in the field and our unique position to further investigate the crosstalk between this newly identified
pathway and other PTMs involved in regulating mitochondrial function. In particular, we will focus our future
studies on the crosstalk between ubiquitination and ADP-ribosylation. These PTMs work in tandem in the
regulation of nuclear genome stability, innate immunity and stress-induced translational regulation. However,
their relationship in regulating mitochondrial function has not yet been investigated. In fact, although the presence
of ADP-ribosylation activity in mitochondria was known for decades, the identity of the mitochondrial ART
enzyme/s has been elusive, hindering more detailed studies on the role and regulation of mitochondrial proteins
through ADP-ribosylation. As we recently identified NEURL4 as a mitochondria-dedicated ADP-ribosyl
transferase under the regulation of stress-induced and GPS2-mediated reprogramming, we are now in the
position of carrying those studies. We propose a research plan spanning two major areas:1) Investigating the
spatial and functional regulation of mitochondria retrograde signaling in response to mitochondrial stress and 2)
Exploring the crosstalk between ubiquitination and ADP-ribosylation in regulating mitochondrial homeostasis.
Our research plan addresses three key problems: i) the spatial regulation of mitochondria retrograde signaling;
ii) the functional contribution of mitochondria retrograde signaling to the regulation of ADP-ribosylation and
ubiquitination across subcellular compartments; iii) the molecular mechanisms underlying the coordinated
regulation of ADP-ribosylation/ ubiquitination. Successful completio...

## Key facts

- **NIH application ID:** 10807018
- **Project number:** 5R35GM149339-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** VALENTINA PERISSI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $439,725
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807018

## Citation

> US National Institutes of Health, RePORTER application 10807018, Coordination of PAR and Ub signaling in mitochondria (5R35GM149339-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10807018. Licensed CC0.

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