Interferon-alpha selectively signals mitochondrial pore opening to allow mitochondrial RNA release in systemic lupus erythematosus: pathophysiological implications.

Mitochondrial dysfunction resulting in mitochondrial DNA (mtDNA) leakage is one of the main triggers of immune responses in systemic lupus erythematosus (SLE). In contrast, mitochondrial RNA (mtRNA) leakage and its role in SLE remains poorly understood. Interferon-alpha (IFN-α) and immune complexes (ICs) are both pathogenic contributors to SLE. Following the detection of increased mtRNA in the serum of patients with SLE, we explored the mechanisms of mtRNA leakage. Exposure to IFN-α at 100 U/ml, a pathophysiological concentration detected in SLE patients with mild to moderate disease activity, resulted in mitochondrial permeability transition pore (mPTP) opening and voltage dependent anion channel 1 (VDAC1) oligomerization, leading to mtRNA leakage and downstream inflammatory pathway activation in bone marrow-derived macrophages (BMDMs) of mice. However, we did not observe the activation of BCL2 antagonist/killer 1 (BAK) and BAK/BCL2-associated X (BAX) (BAX/BAK) pores and mitophagy does not play roles in these effects. Overloaded mitochondrial calcium released from the endoplasmic reticulum is likely responsible for mitochondrial pore opening. Similar effects were observed with ICs treatment. Several commonly recognized events contributing to mitochondrial pore opening such as cell death, apoptosis and changes of mitochondrial membrane potential were not detected and a pan-caspase inhibitor Z-VAD-FMK could not block IFN-α and ICs-induced mtRNA release. Our studies demonstrated an unexpected phenomenon that a pathophysiological concentration of IFN-α and ICs can selectively induce mitochondrial pore opening leading to mtRNA release in primary macrophages.