Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease

Sullivan, E. Madison; Pennington, Edward Ross; Green, William D.; Beck, Melinda A.; Brown, David A.; Shaikh, Saame Raza

doi:10.1093/advances/nmy007

Cited by 62 publications

(54 citation statements)

References 237 publications

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“…Multiple cell-intrinsic mechanisms have been suggested to trigger cell death and the progression to NAFLD [43], [44]. Recently, it has been recognized that impaired hepatic mitochondrial function plays a key role in the progression of hepatocyte death [45]. Chronic lipid accumulation shifts the mitochondrial metabolism to beta-oxidation, and contributes to the overproduction of ROS and mitochondrial metabolism dysfunction [46].…”

Section: Discussionmentioning

confidence: 99%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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Obesity-related non-alcoholic fatty liver disease (NAFLD) is connected with mitochondrial stress and hepatocyte apoptosis. Parkin-related mitophagy sustains mitochondrial homeostasis and hepatocyte viability. However, the contribution and regulatory mechanisms of Parkin-related mitophagy in NAFLD are incompletely understood. Macrophage stimulating 1 (Mst1) is a novel mitophagy upstream regulator which excerbates heart and cancer apoptosisn via repressing mitophagy activity. The aim of our study is to explore whether Mst1 contributes to NAFLD via disrupting Parkin-related mitophagy. A NAFLD model was generated in wild-type (WT) mice and Mst1 knockout (Mst1-KO) mice using high-fat diet (HFD). Cell experiments were conducted via palmitic acid (PA) treatment in the primary hepatocytes. The results in our study demonstrated that Mst1 was significantly upregulated in HFD-treated livers. Genetic ablation of Mst1 attenuated HFD-mediated hepatic injury and sustained hepatocyte viability. Functional studies illustrated that Mst1 knockdown reversed Parkin-related mitophagy and the latter protected mitochondria and hepatocytes against HFD challenge. Besides, we further figured out that Mst1 modulated Parkin expression via the AMPK pathway; blockade of AMPK repressed Parkin-related mitophagy and recalled hepatocytes mitochondrial apoptosis. Altogether, our data identified that NAFLD was closely associated with the defective Parkin-related mitophagy due to Mst1 upregulation. This finding may pave the road to new therapeutic modalities for the treatment of fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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“…The TOMM5 gene, which is a translocase of the outer mitochondrial membrane, was downregulated in both treatments. It has been reported that PUFAs can cause a change in mitochondrial membrane composition and organization that leads to increased production of ROS, which in turn causes peroxidation of membrane phospholipids and mitochondrial dysfunction [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

Peroxidized Linoleic Acid, 13-HPODE, Alters Gene Expression Profile in Intestinal Epithelial Cells

Faizo

Narasimhulu

Forsman

et al. 2021

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Lipid peroxides (LOOHs) abound in processed food and have been implicated in the pathology of diverse diseases including gut, cardiovascular, and cancer diseases. Recently, RNA Sequencing (RNA-seq) has been widely used to profile gene expression. To characterize gene expression and pathway dysregulation upon exposure to peroxidized linoleic acid, we incubated intestinal epithelial cells (Caco-2) with 100 µM of 13-hydroperoxyoctadecadienoic acid (13-HPODE) or linoleic acid (LA) for 24 h. Total RNA was extracted for library preparation and Illumina HiSeq sequencing. We identified 3094 differentially expressed genes (DEGs) in 13-HPODE-treated cells and 2862 DEGs in LA-treated cells relative to untreated cells. We show that 13-HPODE enhanced lipid metabolic pathways, including steroid hormone biosynthesis, PPAR signaling, and bile secretion, which alter lipid uptake and transport. 13-HPODE and LA treatments promoted detoxification mechanisms including cytochrome-P450. Conversely, both treatments suppressed oxidative phosphorylation. We also show that both treatments may promote absorptive cell differentiation and reduce proliferation by suppressing pathways involved in the cell cycle, DNA synthesis/repair and ribosomes, and enhancing focal adhesion. A qRT-PCR analysis of representative DEGs validated the RNA-seq analysis. This study provides insights into mechanisms by which 13-HPODE alters cellular processes and its possible involvement in mitochondrial dysfunction-related disorders and proposes potential therapeutic strategies to treat LOOH-related pathologies.

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“…Modification and remodeling of membrane lipids and raft microdomains may broadly underlie shifts in survival and inflammatory signaling, gene expression, and metabolic and ionic homeostasis [ 1 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], including beneficial effects on gap junctions and connexin-43 [ 22 , 23 , 24 ]. Mitochondrial membranes may additionally be modified [ 25 ], potentially influencing energy and reactive oxygen species (ROS) generation. Nonetheless, how n-3 PUFAs specifically modify the structure and functionality of membrane domains awaits clarification [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

et al. 2020

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Whether dietary omega-3 (n-3) polyunsaturated fatty acid (PUFA) confers cardiac benefit in cardiometabolic disorders is unclear. We test whether dietary -linolenic acid (ALA) enhances myocardial resistance to ischemia-reperfusion (I-R) and responses to ischemic preconditioning (IPC) in type 2 diabetes (T2D); and involvement of conventional PUFA-dependent mechanisms (caveolins/cavins, kinase signaling, mitochondrial function, and inflammation). Eight-week male C57Bl/6 mice received streptozotocin (75 mg/kg) and 21 weeks high-fat/high-carbohydrate feeding. Half received ALA over six weeks. Responses to I-R/IPC were assessed in perfused hearts. Localization and expression of caveolins/cavins, protein kinase B (AKT), and glycogen synthase kinase-3 β (GSK3β); mitochondrial function; and inflammatory mediators were assessed. ALA reduced circulating leptin, without affecting body weight, glycemic dysfunction, or cholesterol. While I-R tolerance was unaltered, paradoxical injury with IPC was reversed to cardioprotection with ALA. However, post-ischemic apoptosis (nucleosome content) appeared unchanged. Benefit was not associated with shifts in localization or expression of caveolins/cavins, p-AKT, p-GSK3β, or mitochondrial function. Despite mixed inflammatory mediator changes, tumor necrosis factor-a (TNF-a) was markedly reduced. Data collectively reveal a novel impact of ALA on cardioprotective dysfunction in T2D mice, unrelated to caveolins/cavins, mitochondrial, or stress kinase modulation. Although evidence suggests inflammatory involvement, the basis of this “un-conventional” protection remains to be identified.

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Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease

Cited by 62 publications

References 237 publications

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

Peroxidized Linoleic Acid, 13-HPODE, Alters Gene Expression Profile in Intestinal Epithelial Cells

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

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