# Regulation of autophagy and mitochondrial permeability by target of rapamycin complex 2

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $649,061

## Abstract

Autophagy is a conserved process by which all eukaryotic cells eliminate defective organelles and molecules,
and is generally regarded as a health- and longevity-promoting process. Mutations in the autophagy machinery
contribute to human conditions such as autoimmune, metabolic, inflammatory, neoplastic, and
neurodegenerative diseases, and prompt changes consistent with premature aging. Conversely, nearly all
genetic and environmental manipulations that extend lifespan do so in a manner dependent upon autophagy.
However, we have determined that autophagy has negative consequences on health when it occurs in the
setting of increased mitochondrial permeability. The net consequence of autophagy in the setting of increased
mitochondrial permeability is shortened lifespan and increased susceptibility to ischemia/reperfusion injury.
There is a critical need to understand the cellular and molecular mechanisms by which mitochondrial
permeability is regulated in order to develop the next generation of interventions to reduce negative impacts of
autophagy in aging and disease. The long-term goal of this project is to determine how mitochondrial
permeability is regulated and to define the consequences of increased mitochondrial permeability on cellular
and organismal dysfunction in aging. Our objective in this particular application is to define how upstream
signaling pathways involved in promoting longevity and reducing disease suppress mitochondrial permeability,
and the consequences this has on autophagy, mitochondrial function, and lifespan. This project will meet this
objective by studying the detailed mechanisms by which mitochondrial permeability is regulated and the
consequences of this regulation. We have determined that defects in signaling in the mTOR complex 2
pathway lead to increases in mitochondrial permeability and autophagy, shortening lifespan and increasing
ischemia/reperfusion injury. The central hypothesis of this proposal is that low mitochondrial permeability is a
central determinant of the effects of autophagy on lifespan and aging-associated diseases. The rationale for
this proposal is that fuller understanding of the regulation of mitochondrial permeability will permit us to target
permeability to promote healthy aging in humans. Guided by preliminary data, we will test our hypothesis in
three specific aims. In Aim 1, we will define the mechanisms by which mitochondrial permeability is decreased
by prolongevity pathways. In Aim 2 we will define the mechanisms by which mitochondrial permeability and
defects in mTOR complex 2 signaling drive autophagy. Aim 3 will determine the mechanism by which the union
of mitochondrial permeability and autophagy shorten lifespan. At the conclusion of these studies, we will have
identified the major mechanisms by which mitochondrial permeability disrupts cellular function and shortens
lifespan. The proposed research is significant because it will have broad implications for rational design of the
n...

## Key facts

- **NIH application ID:** 10241881
- **Project number:** 9R56AG068999-06A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALEXANDER A SOUKAS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $649,061
- **Award type:** 9
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241881

## Citation

> US National Institutes of Health, RePORTER application 10241881, Regulation of autophagy and mitochondrial permeability by target of rapamycin complex 2 (9R56AG068999-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241881. Licensed CC0.

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