# Mitochondrial Stress Signal Transduction from Organelle to Organism

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $323,500

## Abstract

PROJECT SUMMARY
 Neuroendocrine and metabolic stressors threaten cellular and organismal integrity, leading to
maladaptive cellular changes and disease unless met by adaptive remodeling of nuclear gene expression.
Mitochondria are central to these adaptations. Recent findings indicate that mitochondria participate in a three-
step intracellular signal transduction system involving sensing, signal integration and transduction to the
nucleus where they regulate the majority of genes within the human genome. In this way, mitochondria are a
emerging as determinants of cellular and organismal adaptation to common stressors.
 The overall objective of this proposal is to define novel mechanisms of mitochondria-mitochondria and
mitochondria-nuclear signaling leading to gene expression remodeling. To achieve this, my laboratory uses
use drug-inducible inter-organellar linker technology to manipulate mito-mito and mito-nuclear interactions in
muscle cells, coupled to high-resolution quantitative light and electron microscopy approaches to track
organelle interactions. We exploit high-throughput functional assays, metabolomics, and transcriptomics to
visualize and understand the resulting nuclear transcriptional responses patterns to stressors. To disentangle
the relative contributions of mitochondrial network organization and functions to mitochondrial signaling, we
leverage unique trans-mitochondrial cell and animal models, as well as mitochondria-targeted small molecule
antioxidants and pharmacological agents. Candidate signaling pathways will be validated using parallel genetic
and biochemical experiments. Most promising pathways will be extended in follow up studies using a near-
experimental human disease model of primary mitochondrial DNA defects to validate our findings in humans.
 Together, this combined approach will investigate specific components of the mitochondria-nuclear
communication system and their relevance to human disease. This work will establish the physical basis for
gene expression regulation by mitochondria, and serve as the foundation for further work aiming to circumvent
maldaptative cellular and organismal responses to stressors and mitochondrial dysfunction.

## Key facts

- **NIH application ID:** 9925788
- **Project number:** 5R35GM119793-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Martin Picard
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,500
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925788

## Citation

> US National Institutes of Health, RePORTER application 9925788, Mitochondrial Stress Signal Transduction from Organelle to Organism (5R35GM119793-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9925788. Licensed CC0.

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