Cell Death: Fundamental Mechanisms and Roles in Human Disease
The most basic decision that any cell makes is to grow, differentiate, or die. Our laboratory studies fundamental mechanisms of cell death and the roles of cell death in normal biology and human disease. Twelve cell death programs have been recognized to date. Little is understood about how they interconnect mechanistically or integrate functionally to bring about cell death. The overarching goal of our work is to create a more unified model of cell death that integrates seemingly “individual” cell death programs. Our hypothesis is that “individual” cell death programs, which often undergo activation in the same cell, are components of an integrated cell death response that has arisen over evolution.
To gain traction in understanding this integration, we have focused on two cell death programs, mitochondrial-dependent apoptosis and mitochondrial-dependent necrosis. The rationale for choosing these programs is that the sentinel events in each take place within microns of each other at the outer and inner mitochondrial membranes respectively. In addition, both of these programs play important roles in the pathogenesis of the major human diseases.
We have adopted two strategies to understand connections between mitochondrial-dependent apoptosis and necrosis. The first is a candidate approach to identify mediators which are common to both programs and, therefore, may function as “decision points”. These studies have revealed that several canonical regulators of apoptosis, including BAX, ARC, and CASPASE-9, mediate necrosis through distinct mechanisms (Mol Cell, 2004; PNAS, 2007; JBC, 2007; PNAS, 2012; Cell Death Differ, 2014). A second approach has involved genetic screens to better define mitochondrial-dependent necrosis signaling, which remains poorly understood. These have included genome wide CRISPR-based functional screens and protein interaction screens using as bait proteins with known roles in this necrosis pathway. The results of these screens are currently the basis of several ongoing projects involving cell death, metabolism, and other aspects of mitochondrial function.
While the primary focus of the lab is basic mechanisms, we are also interested in translational implications. While some of our work has involved cell and mouse models of cancer (Cell Death Differ, 2005; JBC, 2010; Cancer Res, 2011, PLOS One, 2015) and type 2 diabetes (Diabetes, 2013; Sci Rep, 2017; Dev Cell, 2021), our primary translational focus is heart disease, the major cause of mortality worldwide. A number of years ago, our lab provided the initial evidence that regulated forms of cell death play critical roles in the pathogenesis of myocardial infarction (“heart attack”) (Circulation, 2000; JMCC, 2000; AJP, 2003) and heart failure (JCI, 2003). More recently, the lab contributed to the development of small molecule and peptide drug prototypes that inhibit cell death and may provide the basis for new therapies for heart diseases and other conditions (Nature, 2016; Science, 2018; Nat Chem Biol, 2019; Nat Cancer, 2020). We continue to use the in vivo myocardial infarction model in our current work aimed at unifying cell death mechanisms because at least 6 cell death programs are activated in this syndrome.
Projects currently in progress:
1. Mechanism of CASPASE-9-mediated necrosis
2. Functions of BCL-2 proteins at the outer and inner mitochondrial membranes
3. Regulation of ferroptosis by OPA1
4. Contributions of necroptosis and ferroptosis to myocardial infarction
5. Mitochondrial-ER/SR interactions in regulating cell death and metabolism
6. Role of the mitochondrial ATP synthase in bioenergetics and cell death
7. Identification of the mitochondrial permeability transition pore
8. Determinants of the senescence versus cell death “decision” in aging tissues