Mitochondrial dysfunction, characterized by the persistent elevation of the mitochondrial transmembrane potential, lack of mitochondrial fission, oxidative stress and decreased energy production plays a fundamental role in abnormal T-cell activation in patients with SLE. Mitochondrial fission is not only needed to create new mitochondria, but also to remove damaged mitochondria during high levels of cellular stress. Why in T cells of SLE patients mitochondrial fission is inhibited and mitochondria accumulate and promote cell death is not known. Under healthy conditions fission is induced by dynamin-related protein 1 (Drp1) upon translocation from cytoplasm to mitochondria. Latest studies suggest that Drp1 activation and recruitment to mitochondria is mediated by Cardiolipin (CL), a lipid uniquely found in mitochondrial inner and outer membranes. Although autoantibodies against CL and related phospholipids are known biomarkers of SLE, the function of CL in SLE cells has never been investigated in the past. Neither is it known whether CL interaction with Drp1 is inhibited in SLE and what cellular factors could inhibit this interaction. Our preliminary data shows that oxidative stress alone can induce oligomerization of MAVS, a mitochondrial antiviral signaling protein that is normally activated during viral infections. We show that lymphocytes from SLE patients have spontaneously oligomerized MAVS, which can associate with CL and that mitochondria with oligomerized MAVS do not undergo Drp1-dependent fission and do not engage in mitophagy. We thus hypothesize that MAVS oligomers occlude CL from binding to Drp1 and therefore hinder the segregation of normal and dysfunctional mitochondria. We propose that MitoQ and mitochondria targeted peptides, which bind to CL will restore fission and mitophagy. Our work will establish for the first time the missing link between type I IFN signature and the presence of anti-CL autoantibodies in SLE patients.
Cellular build-up of old and dysfunctional mitochondria, the organelles responsible for production of energy, is associated with a number of pathologies in SLE. This application explores a new lipid damage signal, cardiolipin - that we propose eradicates T cell mitochondria, causes cell death and promotes immune responses. By deciphering cardiolipin signaling in SLE we will able to broaden the spectrum of therapeutics for SLE by existing inhibitors of cardiolipin dysfunction.
