Bax and Bak Jointly Control Survival and Dampen the Early Unfolded Protein Response in Pancreatic β-Cells Under Glucolipotoxic Stress
This week we profile a recent publication in Scientific Reports from Sarah White (pictured, right)
in the laboratory of Dr. Dan Luciani (left) at the BC Children’s Hospital Research Institute.
Can you provide a brief overview of your lab’s current research focus?
Research in the Luciani lab seeks to understand the cellular basis of diabetes; a chronic metabolic disease that affects more than 460 million people world-wide. Specifically, we study the mechanisms that regulate the function and survival of the pancreatic β-cells that release insulin in response to increases in blood sugar (glucose) following a meal. This insulin provides a feedback signal that is needed for blood glucose levels to be returned to normal. Dysfunction and/or death of β-cells therefore results in chronic hyperglycemia, which is what defines diabetes and causes the many serious complications of the disease. Much of our research focuses on a group of cell survival-regulating proteins called the “Bcl-2 family”. We study how these proteins control β-cell apoptosis (a regulated process of cellular suicide) and we are identifying new mechanisms by which several members of the family regulate normal β-cell function, as well as early stages of β-cell failure. The ultimate goal of this research is to identify therapeutic targets for protection of β-cells and prevention of diabetes.
What is the significance of the findings in this publication?
This work has shed new light on the molecular machinery that controls β-cell survival. We compared β-cells with four distinct genetic changes to determine the individual and combined contribution of two Bcl-2 family ‘executioner’ proteins, Bax and Bak, to β-cell death induced by the type of glucose and lipid-induced stress the β-cells experience in the development of type 2 diabetes. Bax and Bak are generally believed to have the same function of permeabilizing the cells mitochondrial membrane to trigger apoptosis. We discovered that their comparative involvement in this process can depend on the type of stress the β-cell experiences. Additionally, we found that Bax and Bak affect the strength of stress signals that can determine if β-cells undergo adaptation or maladaptation under conditions of nutrient excess. This finding provides additional evidence that Bcl-2 family proteins have much broader roles in regulating cellular fate than previously recognized.
What are the next steps for this research?
We continue to investigate the roles of Bax, Bak and other Bcl-2 family apoptosis proteins in pancreatic β-cells. As part of this, we are asking whether these proteins may direct changes in the cells’ mitochondrial health and affect the development of a diabetes-promoting state in which the β-cells undergo premature aging (senescence) under nutrient stress. The answers to these questions have significant implications for efforts to target senescent cells in diabetes and other diseases.
This work was funded by:
We gratefully acknowledge support in form of research grants from Diabetes Canada and the Canadian Institutes of Health Research (CIHR), as well as salary support from the BC Children’s Hospital Research Institute (BCCHR).