Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock

Brown adipose tissue (BAT) is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine BAT thermogenic capacity prior to environmental cold are unknown. Here we show that Histone Deacetylase 3 (HDAC3) is required to activate BAT enhancers to ensure thermogenic aptitude. Mice with BAT-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is also marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of Estrogen-Related Receptor α (ERRα) in BAT. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Pgc-1α and OXPHOS genes. Importantly, HDAC3 promotes the basal transcription of these genes independent of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged upon exposure to dangerously cold temperature.

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“…Sodium Azide (2.5 mM) was used to assess the contribution of leak respiration independent of CIV. 37,38 …”

Section: Methodsmentioning

confidence: 99%

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Emmett

Lim

Jager

et al. 2017

Nature

Self Cite

161

163

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“…Resveratrol attenuates hepatocyte (Powell et al , 2014; Yu et al , 2010b), intestinal (Yu et al , 2011), lung (Wu et al , 2008), kidney(Wang et al , 2015a) and endothelial (Yu et al , 2010a) injury during hemorrhage induced ischemia. The accumulation and activity of the mitochondrial/glycolytic master switch in hypoxia, HIF1-α, is regulated by SIRT1 in hypoxic hepatocellular (Laemmle et al , 2012), kidney, colorectal, gastric cancer, cervical, lung, fibrosarcoma, glioblastoma and prostate cancer cells (Yoon et al , 2014).…”

Section: Pharmacologic Therapiesmentioning

confidence: 99%

Mitochondrial function in hypoxic ischemic injury and influence of aging

Ham

Raju

2017

Progress in Neurobiology

282

205

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Mitochondria are a major target in hypoxic/ischemic injury. Mitochondrial impairment increases with age leading to dysregulation of molecular pathways linked to mitochondria. The perturbation of mitochondrial homeostasis and cellular energetics worsens outcome following hypoxic-ischemic insults in elderly individuals. In response to acute injury conditions, cellular machinery relies on rapid adaptations by modulating posttranslational modifications. Therefore, post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK play a critical role in the control of the glycolytic-mitochondrial energy axis in response to hypoxic-ischemic conditions. The deficiency of oxygen and nutrients leads to decreased energetic reliance on mitochondria, promoting glycolysis. The combination of pseudohypoxia, declining autophagy, and dysregulation of stress responses with aging adds to impaired host response to hypoxic-ischemic injury. Furthermore, intermitochondrial signal propagation and tissue wide oscillations in mitochondrial metabolism in response to oxidative stress are emerging as vital to cellular energetics. Recently reported intercellular transport of mitochondria through tunneling nanotubes also play a role in the response to and treatments for ischemic injury. In this review we attempt to provide an overview of some of the molecular mechanisms and potential therapies involved in the alteration of cellular energetics with aging and injury with a neurobiological perspective.

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“…Furthermore, the decreased oxygen availability in tissues result in declined OXPHOS activity and ATP production. To further confirm the dysregulation of mitochondrial metabolism in HI, our laboratory and others have demonstrated that agents which potentiate mitochondrial function can improve organ function and survival following HI in experimental models of hemorrhagic shock (18–20). However, the understanding of the role of mitochondria in HI is still evolving and the effect of HI on splenocyte mitochondrial respiration remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock

Warren¹,

Subramani²,

Schwartz³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The regulation of mitochondrial function is critical in cellular homeostasis following hemorrhagic shock. Hemorrhagic shock leads to fluid loss and reduced availability of oxygen and nutrients to tissues. The spleen is a secondary lymphoid organ playing a key role in ‘filtering the blood’ and in the innate and adaptive immune responses. To understand the molecular basis of hemorrhagic shock, we investigated the changes in splenocyte mitochondrial respiration, and concomitant immune and metabolic alterations. The hemorrhagic injury (HI) in our rat model was induced by bleeding 60% of the total blood volume followed by resuscitation with Ringers lactate. Another group of animals was subjected to hemorrhage, but did not receive fluid resuscitation. Oxygen consumption rate of splenocytes were determined using a Seahorse analyzer. We found a significantly reduced oxygen consumption rate in splenocytes following HI compared to sham operated rats. The mitochondrial stress test revealed a decreased basal oxygen consumption rate, ATP production, maximal respiration and spare respiratory capacity. The mitochondrial membrane potential, and citrate synthase activity, were also reduced in the splenocytes following HI. Hypoxic response in the splenocyte was confirmed by increased gene expression of Hif1α. Elevated level of mitochondrial stress protein, hsp60 and induction of high mobility group box1 protein (HMGB1) were observed in splenocytes following HI. An increased inflammatory response was demonstrated by significantly increased expression of IL-6, IFN-β, Mip-1α, IL-10 and NFκbp65. In summary, we conclude that splenocyte oxidative phosphorylation and metabolism were severely compromised following HI.

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Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock

Cited by 60 publications

References 37 publications

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Mitochondrial function in hypoxic ischemic injury and influence of aging

Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock

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