New insights into the role of mitochondria in autoimmune diseases

2019

Challenge

Autoimmune diseases are extremely difficult to treat, and currently used therapies often have problematic health effects of their own. For example, glucocorticoids, which have been the mainstay therapy for many autoimmune diseases for almost half a century, have significant long-term harmful effects, including weakening of the immune system, heart disease, and bone loss. Approximately 24 million Americans are affected by an autoimmune disease, and over the past few decades there has been little progress in identifying novel therapeutic targets for these illnesses.

Advance

Mitochondrial DNA (mtDNA) normally stays within mitochondria, energy-producing structures inside cells. However, it can be released from the mitochondria into the cell in response to stress. When this happens, the mtDNA can trigger an overactive immune response, as occurs in autoimmune diseases. IRP researchers led by senior investigator Jay H. Chung, M.D., Ph.D., discovered that when cells are stressed, mtDNA escapes through mitochondrial pores formed by the mitochondria’s voltage-dependent anion channels (VDACs), which are passages through the mitochondrial outer membrane that allow charged atoms to pass through them. In mice bred to have symptoms resembling the autoimmune disease lupus, an inhibitor of VDAC pores reduced mtDNA release, tamped down the resulting immune response, and reduced the severity of the animals’ symptoms.

Impact

These findings show a novel mechanism by which pores formed on stressed mitochondria release mtDNA into the cell and trigger a damaging immune response. Therefore, this work provides important insights into the link between mitochondrial stress and the immune system and opens up new research avenues into this relationship. More importantly, it reveals a novel strategy for treating autoimmune diseases.

Publications

Kim J, Gupta R, P. Blanco L, Yang S, Shteinfer-Kuzmine A, Wang K, Zhu J,7, Yoon H, Wang X, Kerkhofs M, Kang H, Brown A, Park S, Xu X, Zandee van Rilland E, Kim M, Cohen J, Kaplan M, Shoshan-Barmatz V, Chung J. (2019). VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science. Dec 20;366(6472):1531-1536.