# Elucidating the mechanism of hypoxia rescue of mitochondrial dysfunction

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $23,102

## Abstract

Project Summary/Abstract
The mitochondrial respiratory chain (RC) is the central apparatus enabling mitochondria to
undergo oxidative phosphorylation (OXPHOS) and supply cellular energy. Defective RCs result
in a variety of potentially devastating inborn errors of metabolism with no proven effective
treatment. Additionally, aging and many common age-related diseases including cancer, type 2
diabetes, Alzheimer’s and Parkinson’s diseases also exhibit notable decreases in RC activity.
Recent findings from our laboratory show that cells have an innate capability for coping with
defective RCs that is only accessible upon activation of the hypoxia response, a genetic
program evolved to adapt cells to limited oxygen availability. Growth defects in cultured cells
treated with RC inhibitors are rescued with activation of the hypoxia response. Strikingly, this
rescue is recapitulated in a genetic mouse model of pediatric mitochondrial disease featuring a
dysfunctional RC, attesting to the generalizability of this effect. Mice lacking a key complex I
subunit within the RC develop a fatally progressive encephalopathy and die after ~60 days
exposure to normal oxygen levels, but neurodegeneration is prevented and even reversed after
chronic exposure to hypoxia, with longevity increased to ~ 270 days. As the hypoxia response
upregulates hundreds of individual genes, mechanistically it remains unclear which genes and
what processes defend a cell against RC dysfunction. This proposal aims to identify the
molecular players within the hypoxia response that enable cells to cope with a defective RC.
The first specific aim will explore the genetic effectors of the hypoxia rescue of RC dysfunction
by both targeted and non-targeted approaches, examining the rescue effect in clonal knockouts
of known hypoxia response factors and utilizing whole-genome screens to identify novel genetic
effectors. The second specific aim will investigate the direct metabolic consequences arising
from hypoxic genetic reprogramming amidst RC dysfunction by combining genetic perturbations
and liquid chromatography-mass spectrometry (LC-MS) metabolite profiling of cellular extracts
and spent media over time. Together, these complementary approaches will 1) shed new insight
into the endogenous mechanisms by which cells can protect against a faulty RC under
exposure to low oxygen, 2) refine our understanding of the key cellular vulnerabilities resulting
from RC dysfunction which may lead to pathology in a variety of contexts, and 3) propose new
therapeutic targets that may be applicable generally to a wide spectrum of disorders exhibiting
mitochondrial dysfunction.

## Key facts

- **NIH application ID:** 10204505
- **Project number:** 3F32GM128259-02S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephanie Shih-Min Lam
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $23,102
- **Award type:** 3
- **Project period:** 2018-06-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204505

## Citation

> US National Institutes of Health, RePORTER application 10204505, Elucidating the mechanism of hypoxia rescue of mitochondrial dysfunction (3F32GM128259-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10204505. Licensed CC0.

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