Mitochondrial function in hypoxic ischemic injury and influence of aging

Ham, P. Benson; Raju, Raghavan

doi:10.1016/j.pneurobio.2016.06.006

Cited by 255 publications

(193 citation statements)

References 460 publications

(554 reference statements)

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“…Mitochondria are a major target in hypoxic/ischemic injury and play critical functions in the response to hypoxia, ischemia and reperfusion (Nanayakkara et al, 2015; Ham and Raju, 2016). Perturbation of mitochondrial homeostasis and cellular energetics worsens the outcome following hypoxic-ischemic insults (Nanayakkara et al, 2015; García-Rivas and Torre-Amione, 2009).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

Zhang

Ren

et al. 2016

eLife

154

153

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Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.DOI: http://dx.doi.org/10.7554/eLife.21407.001

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Section: Discussionmentioning

confidence: 99%

Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

Zhang

Ren

et al. 2016

eLife

154

153

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“…Our recent studies demonstrated a significant increase in the plasma levels of cytokines such as IL-6, TNF-α and IL-10 and activation of NF-κb (34). The hypoxic response of the host is complex as reduced oxygen availability can lead to altered mitochondrial energy metabolism as well as an inflammatory trigger (35, 36). The spleen is an organ that is important in both adaptive and innate immunity (37) and the hypoxic effect of HI on mitochondrial respiration in splenocytes has not been investigated.…”

Section: Discussionmentioning

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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“…In addition, it was shown resveratrol has protective effect against cardiotoxicity induced by doxorubicin such as reduction in tissue damage and serum cardiac enzyme activities, preserving mitochondrial morphology and inherent anti-oxidant capacity [14]. Furthermore, the neuroprotective effects of resveratrol have been demonstrated in several in vitro and in vivo models of AD [15], which may be linked either directly or indirectly to protection against mitochondrial dysfunction in aging [16].…”

Section: Introductionmentioning

confidence: 99%