# Mitochondrial Integrated Stress Response in Neurological Diseases

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $1,068,698

## Abstract

Mitochondria play essential roles in cell biology because are central hubs of most metabolic pathways. They are
not only essential for energy conversion, but also for the biosynthesis and catabolism of virtually all cell
constituents. Mitochondrial dysfunction causes havoc in all cells, but especially in those cell types that are highly
dependent on mitochondrial energetic and metabolic functions, such as neurons and glia. Genetic alterations of
the mitochondrial proteome, which includes more than 1000 proteins, encoded by both the nuclear and the
mitochondrial genomes, result in primary mitochondrial disorders. These diseases, for which there is currently
no effective treatment, result in severe and often fatal neurodegeneration. Mitochondrial dysfunction also plays
a role in the pathogenesis of many age-related neurodegenerative disorders, such as Alzheimer and Parkinson
disease and ALS. Therefore, addressing therapeutically the consequences of mitochondrial dysfunction could
have a profound impact on the treatment of many human disorders. A major challenge in devising effective
treatments for mitochondrial encephalopathies is our limited understanding of the ramifications of the effects of
mitochondrial dysfunction. The conventional view that these disorders are caused simply by energy failure is
inadequate, as it is becoming increasingly clear that mitochondrial dysfunction affects much more than just ATP
generation and leads to an extensive rewiring of cell metabolism. An exciting new development in the field is the
observation that various types of mitochondrial dysfunction activate transcriptional and metabolic responses that
involve multiple stress signaling pathways. We and others have identified a “mitochondrial integrated stress
response” (mtISR) in diverse genetic forms of mitochondrial disorders, suggesting that mtISR is strongly
associated with mitochondrial diseases and a potential pathogenic common denominator. We postulate that,
while in the short term these responses may be compensatory, if sustained and unresolved, they become
maladaptive and causes imbalances of key metabolites, which may be more detrimental than the energy defect
itself. While we now fully appreciate these maladaptive mechanisms in peripheral tissues, such as muscle and
heart, very little is known about them in the CNS affected by mitochondrial encephalopathies. A deeper
knowledge of the characteristics and the consequences of the mtISR in the CNS is needed to understand its
pathogenic significance and develop targets therapeutic strategies. Our research group has a long-standing
commitment to investigating the pathogenic mechanisms of mitochondrial diseases and we have accumulated
over two decades of expertise in studying the mechanisms of mitochondrial encephalopathies and mitochondrial
dysfunction in neurodegeneration. In this R35 application, we focus on fundamental gaps in knowledge on the
mtISR in mitochondrial encephalopathies by studying disease model...

## Key facts

- **NIH application ID:** 10829417
- **Project number:** 5R35NS122209-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Giovanni Manfredi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,068,698
- **Award type:** 5
- **Project period:** 2021-05-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829417

## Citation

> US National Institutes of Health, RePORTER application 10829417, Mitochondrial Integrated Stress Response in Neurological Diseases (5R35NS122209-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10829417. Licensed CC0.

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