Delta‐6 desaturase inhibition reverses cardiolipin remodeling and hypertrophy, but not mitochondrial dysfunction, in the aged mouse heart

Abstract

Alterations in the fatty acid composition of cardiolipin (CL), a mitochondrial phospholipid, may contribute to mitochondrial dysfunction associated with myocardial aging, but its mechanism and role in this process remains unclear. We hypothesized that CL remodeling in the aged heart, characterized by a loss of linoleic acid (LA) and increase in highly unsaturated fatty acids (HUFAs), results from increased activity of delta 6‐desaturase (D6D), which catalyzes the production of HUFAs from essential fatty acids such as LA. Aged (24 mo) C57Bl/6 mice were administered a selective D6D inhibitor (SC‐26196, 100 mpk/d; SC) or no drug for 4 weeks, followed by isolation of cardiac subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria for assessment of respiratory function and CL composition. Aged hearts exhibited a classic pattern of CL remodeling in IFM, but not SSM, which paralleled a 25% loss in state 3 respiration in IFM only. SC reversed CL remodeling in IFM, but had no effect on mitochondrial respiration. Interestingly, SC also reversed left ventricular dilatation, reduced heart weight and attenuated contractile dysfunction in aged mice. These studies indicate that D6D plays a pivotal role in CL remodeling in the aged heart, but argue against the role of this process in mitochondrial dysfunction. The mechanism by which D6D influences cardiac remodeling and function warrants further investigation. Funding: AHA