Mitochondrial alterations in sirtuin1 heterozygous mice fed high fat diet and melatonin

Abstract

Silent information regulator 1 (Sirt1), belongs to a family of class III histone deacetylase, which regulates the transcription of genes involved in aging, metabolism and mitochondriogenesis [1]. Its decreased expression/activity in heterozygous Sirt 1+/- mice (HET) has been previously associated to abnormal lipid metabolism, disrupted autophagy and mitochondrial damage in the liver [2]. In this study we focus on the mitochondria quality in other crucial organs like the heart and the kidney in HET mice placed on obesogenic diet (HFD-58% lard) plus or not melatonin (MEL) (10 mg/kg) in drinking water for 16 weeks, in comparison with C57BL/6J mice (WT) receiving the same treatment. Interstitial fibrosis was assessed by Masson trichrome staining, lipid peroxidation and mitochondrial markers by 4HNE, HSP60, Mitofusin 2 and TOM20 immunostaining-ABC-peroxidase. Furthermore, TEM analysis best characterized mitochondria shape and cristae quality [3]. Main results were that MEL alleviated interstitial fibrosis and lipid peroxidation in WT HFD but not in HET HFD. Ultrastructural analysis demonstrated lipid bodies, calcification granules, abnormal mitophagy and intermyofibrillar mitochondria in the heart. Similarly, donut-like mitochondria with disrupted cristae and aberrant myelin-like figures in proximal renal tubules of HET HFD mice were found. All these data suggest that 1) mitochondria morphology is deeply affected in mice lacking full SIRT1 expression; 2) antioxidant melatonin is ineffective in HET mice model of obesity. However, further experimental approaches are warranted to reveal molecular mechanisms involved in oxidative impairment and mitophagy disruption in these mice.