# Mechanism of Bax/Bak Activation During Apoptosis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $320,250

## Abstract

Apoptosis is an essential cellular death program that controls proper development and maintains homeostasis.
Aberrant regulation of apoptosis contributes to many diseases, such as neurodegeneration, autoimmune
diseases, and cancer. The mitochondria-dependent pathway is a major apoptotic pathway, and is primarily
regulated and executed by the Bcl-2 family proteins. The Bcl-2 family includes five anti-apoptotic members, two
effector proteins Bax and Bak, and eight pro-apoptotic BH3-only proteins. They control the mitochondrial
pathway at the step of mitochondrial outer membrane permeabilization (MOMP), a central control point leading
to apoptosis. Our long term goal is to elucidate the signaling pathways and molecular mechanisms
responsible for mitochondria-dependent apoptosis, and provide positive impact on the development of more
potent and specific therapies against apoptosis-related diseases. While genetic and biochemical studies have
long established the role of Bax and Bak as two essential effectors of MOMP, the mechanism of Bax/Bak
activation, commonly considered the life-to-death switch of the cells, has been intensively investigated in the
past two decades. The current consensus is that while all pro-apoptotic BH3-only proteins suppress the anti-
apoptotic Bcl-2 proteins, a subset of BH3-only proteins directly engage and activate Bax and Bak during
apoptosis. However, in our preliminary studies, we provide genetic evidence suggesting that such a BH3-only
protein-mediated direct activation is not necessary for Bax/Bak activation and apoptosis. Instead, our results
suggest that upon the BH3-only protein-mediated neutralization of the anti-apoptotic Bcl-2 proteins, Bax/Bak
undergo a membrane-dependent, spontaneous activation process. Based on our preliminary studies, we
propose a new model of Bax/Bak activation, which will be examined primarily by genetics, cell biology, and
biochemical approaches. The following three Aims are proposed. In Aim 1, we will examine the role of the
BH3-only proteins and other potential direct activators in Bax/Bak activation following the inactivation of anti-
apoptotic Bcl-2 proteins. In Aim 2, we will investigate the involvement of mitochondrial outer membrane in the
regulation of Bax/Bak activation. In Aim 3, we will investigate the mechanism of anti-apoptotic Bcl-2 protein-
mediated suppression of the Bax/Bak activation. Overall, our proposed studies are expected to elucidate the
mechanism of Bax/Bak activation during apoptosis. This proposal may not only unravel one of the long
standing mysteries in apoptosis research, but also provide novel targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10004152
- **Project number:** 5R01GM118437-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Xu Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $320,250
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004152

## Citation

> US National Institutes of Health, RePORTER application 10004152, Mechanism of Bax/Bak Activation During Apoptosis (5R01GM118437-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10004152. Licensed CC0.

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