Metabolic Control of Autoimmunity in the Liver

Abstract

Autophagy,literally meaning “self-eating,” is an integral part of cellularturnover of damaged organelles and proteins.This process is inextricably linked to mitochondrial function and turnover. Mitochondria can be degraded viaautophagy, known as mitophagy, as well as donate lipid membraneto generate autophagosomes fordigestingother organelles and proteins. On a larger scale, autophagy is essential for organ homeostasis. In the liver, autophagy ensures the turnover of damaged mitochondria that may otherwise increase oxidative stress which modifies DNA, proteins, and lipids resulting in the production of autoantigens or neoplasia. We investigated the role of autophagy and mitochondrial dysfunction prior to disease onset in mouse models of systemic lupus erythematosus (SLE). Patients and mice with SLE exhibit overexpression of transaldolase (TAL) and show predisposition to anti-phospholipid antibody production and associated liver diseases, including hepatocellular carcinoma. Wediscovered deficient mitophagy in the liver of lupus-prone mice prior to disease onset. Furthermore, these mice had increased mitochondrial respirationwith concomitant inner membrane hyperpolarization. These changes were coupled to overexpression of Rab4A, which depletes Drp1and thus inhibitsmitophagy.In addition,activation of complex I of the mechanistic target of rapamycin (mTORC1)was noted along with enhanced production of autoantibodies against mitochondrial phospholipids in lupus-prone mice. These changes were reversed by blockade of mTORC1 by rapamycin treatment in vivo. We then examined the role of TAL, a key enzyme of the pentose phosphate pathway (PPP) in mitochondrial dysfunction and oxidative stress. TAL-deficientmice showedincreased mitochondrial electron transport chain (ETC) activity and mTORC1 activation andreduced autophagy.Since inactivation of TAL caused oxidative stress via depletion of NADPH, we tested the hypothesis that aldose reductase(AR), a NADPH dependent enzymecan correct this metabolic defect without reversing the accumulation of TAL-specific substrates, sedoheptulose 7-phosphate and erythrose 4-phosphate. Moreover, deletion of AR reversed mTORC1 activation without affecting enhanced mitochondrial ETC activity or diminished autophagy. On a more global scale, predisposition to neoplasia and acetaminophen-induced liver failurewere reversed, while anti-phospholipid autoantibody production and liver fibrosis persisted in TAL/AR double-knockout mice indicatingthat the PPPmay act as a metabolic rheostat of organ-specific disease pathogenesis.