# Probing the Relationship Between Protein Kinase C and mTOR in Mitochondrial Function

> **NIH NIH F32** · UNIVERSITY OF WASHINGTON · 2021 · $69,306

## Abstract

Mitochondrial dysfunction pathologically causes many incurable diseases such as the neurometabolic
disease Leigh Syndrome almost certainly resulting in childhood death. It additionally exacerbates most late-
onset diseases such as cancer, Alzheimer's, and heart disease. To help fill the unmet medical need for new
treatments that prevent the onset of these diseases, the Kaeberlein Group focuses on elucidating novel
mechanisms of mitochondrial disease progression and the development of effective pharmacological
interventions with specific molecular targets. To do this, we utilize the leading mammalian model of Leigh
Syndrome missing the electron transport chain structural protein subunit NDUFS4. These mice exhibit a severe
neurodegenerative phenotype and premature death. My group recently discovered the FDA-approved mTOR
inhibitor rapamycin can remarkably attenuate disease progression and increase the mean lifespan by ~50% in
these mice. Rapamycin also extends lifespan in wild type mice, delays the onset of cancer in cancer-prone mice,
improves neurological function in Alzheimer's models, and prevents other hallmarks of aging. We amassed
significant evidence that this small molecule remodels the metabolome in brain tissue isolated from NDUFS4-
KO mice, including decreased NAD+ levels and a switch from glycolysis to amino acid catabolism.
 My group recently observed severe deactivation of the mTOR and protein kinase C (PKC) pathways in
rapamycin-treated NDUFS4-KO mice by phosphoproteomic analysis. This data revealed an unknown
relationship between the mTORC2 and PKC signaling pathways in mitochondrial physiology. I have acquired
evidence that inhibition of PKCs extends lifespan in these mice, establishing its role in the pathology of
mitochondrial disease. This proposal will characterize this relationship, elucidate its mechanistic implications,
and discover new pharmacological interventions to prevent mitochondrial disease progression taking a
hypothesis driven approach based on my preliminary data. I will illuminate the role of calcium-dependent
signaling in mitochondria-associated ER membranes and probe the importance of individual PKCs in the disease
phenotype through chemical and genetic inhibition. Collectively, these complementary basic science studies will
provide a better understanding of mitochondrial biology, uncover the role of signaling pathways in mitochondrial
disease, and illuminate novel mechanisms of interorganellar communication. The achievement of these aims
may even have broad implications in the prevention of diseases of normative aging such as Alzheimer’s, cancer,
and heart disease.

## Key facts

- **NIH application ID:** 10062521
- **Project number:** 5F32NS110109-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Anthony Steven Grillo
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062521

## Citation

> US National Institutes of Health, RePORTER application 10062521, Probing the Relationship Between Protein Kinase C and mTOR in Mitochondrial Function (5F32NS110109-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10062521. Licensed CC0.

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