2014 Metabolism, General Immune System Function
Mitochondrial Autophagy in the Control of Systemic Autoimmunity
The study and what it means to patients
In white blood cells from lupus patients, the cell’s essential energy producing factories (mitochondria) do not work as well as they should. We are studying whether this is caused by a failure of white blood cells to selective clearing the mitochondria that do not function properly (by a process known as autophagy), and whether autophagy defects have a role in the development of lupus. Our work will establish whether therapies aimed at correcting autophagy defects have potential benefits in lupus.
Mitochondria are essential for energy production and proper cell functions. In normal cells, mitochondria that no longer work well are digested and cleared by a process called autophagy (meaning self-eating). Autophagy is important for quality control of the cell’s components including mitochondria.
However, in the white blood cells of patients with lupus, this process is not efficient so abnormal mitochondria do not get renewed. We think that this is directly linked to the development of autoimmunity. Our study in mice aims to figure out how autophagy protects white blood cells from becoming reactive to the body’s own tissues and causing autoimmune diseases such as lupus. This work will help to establish whether therapies that promote autophagy of abnormal mitochondria can prevent lupus by stopping immune cells from reacting to the body’s own tissues.
Genome-wide association studies have identified an autophagy gene, Atg5, as one of the susceptibility loci in SLE, however, the functional significance of this finding is not yet established. Interestingly, T cells from SLE patients are resistant to the induction of autophagy. SLE T cells harbor increased mitochondrial contents, leading to dysregulated mitochondrial function and increased autoimmune potential in T cells. Whether increased mitochondrial accumulation is caused by defective autophagy has not been determined. We found that knockouts of two Bcl-2 family members that regulate mitochondrial autophagy, Nix and Bnip3, resulted in abnormal T-cell activation and the development of autoimmune responses. We hypothesize that autophagy of mitochondria is essential for mitochondrial quality control in T cells, while defects in this process leads to abnormal T cell activation and the induction of autoimmunity. We propose the following studies: 1. To test the hypothesis that defective mitochondrial autophagy leads to abnormal T cell activation; 2. To test the hypothesis that deficiency in autophagy of defective mitochondria in T cells leads to development of autoimmunity in vivo; and 3. To examine the molecular mechanisms for Nix and Bnip3 in mediating mitochondrial autophagy in T cells.