scholarly journals Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3

2017 ◽  
Vol 114 (45) ◽  
pp. 11908-11913 ◽  
Author(s):  
Hengxun Hu ◽  
Jinliang Nan ◽  
Yong Sun ◽  
Dan Zhu ◽  
Changchen Xiao ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Oxygen Consumption ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Cell Protection ◽  
Causative Relationship ◽  
R Process ◽  
And Function

The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors ofN,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2level in the cytosol, but not in the mitochondria. Importantly, increased H2O2served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.

Thyroid hormone in the frontier of cell protection, survival and functional recovery

2015 ◽  
Vol 17 ◽  
Author(s):  
Luis A. Videla ◽  
Virginia Fernández ◽  
Pamela Cornejo ◽  
Romina Vargas ◽  
Iván Castillo
Keyword(s):  
Thyroid Hormone ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Bipolar Disorders ◽  
Nuclear Factor Κb ◽  
Ros Generation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cell Protection ◽  
Beneficial Effects

Thyroid hormone (TH) exerts important actions on cellular energy metabolism, accelerating O2consumption with consequent reactive oxygen species (ROS) generation and redox signalling affording cell protection, a response that is contributed by redox-independent mechanisms. These processes underlie genomic and non-genomic pathways, which are integrated and exhibit hierarchical organisation. ROS production led to the activation of the redox-sensitive transcription factors nuclear factor-κB, signal transducer and activator of transcription 3, activating protein 1 and nuclear factor erythroid 2-related factor 2, promoting cell protection and survival by TH. These features involve enhancement in the homeostatic potential including antioxidant, antiapoptotic, antiinflammatory and cell proliferation responses, besides higher detoxification capabilities and energy supply through AMP-activated protein kinase upregulation. The above aspects constitute the molecular basis for TH-induced preconditioning of the liver that exerts protection against ischemia-reperfusion injury, a strategy also observed in extrahepatic organs of experimental animals and with other types of injury, which awaits application in the clinical setting. Noteworthy, re-adjusting TH to normal levels results in several beneficial effects; for example, it lengthens the cold storage time of organs for transplantation from brain-dead donors; allows a superior neurological outcome in infants of <28 weeks of gestation; reduces the cognitive side-effects of lithium and improves electroconvulsive therapy in patients with bipolar disorders.

scholarly journals Mitofusin2 (MFN2) Preserves Mitochondrial Integrity and Function in Megakaryocytes and Platelets

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3137-3137
Author(s):  
Shancy P Jacob ◽  
Yasuhiro Kosaka ◽  
Seema Bhatlekar ◽  
Alexandra Moody ◽  
Victoria Moody ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Complex I ◽  
Association Studies ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Genome Wide Association Studies ◽  
Advisory Committees ◽  
Human Cord Blood ◽  
Mitochondrial Functions ◽  
And Function

Abstract Genome wide association studies (GWAS) have associated mitochondria related loci with platelet numbers, function, and CVD. However, causality has not been established for many of these variants, and their mechanism and functional consequences are unknown. One such variant, MFN2 eQTL rs1474868 (T/T), has been associated with reduced platelet counts and reduced expression (5 fold) of MFN2 RNA in platelets. We show here that the MFN2 T/T variant corresponds with significantly reduced MFN2 protein in platelets. This difference contributes to a significant correlation between MFN2 RNA levels and mitochondrial load and potential in platelets. MFN2 RNA is also reduced by T/T in human cord blood derived megakaryocytes resulting in unfused mitochondria and impaired megakaryopoiesis. Using platelet/megakaryocyte specific Mfn2-/- (Mfn2 KO) mice, we show that Mfn2 impacts platelet numbers, activation and function by regulating mitochondrial energetics. Platelets without Mfn2 had reduced mitochondrial membrane potential and significantly reduced platelet lifespan (P&lt;0.01) that was attributed to an increased rate of phosphatidylserine (PS) flipping (P=0.01). Increased RNA expression with conversely reduced protein expression of Ndufb8 (P&lt;0.01), an index nuclear encoded complex I subunit that is stable only in a fully assembled complex I, suggested a defect in complex I assembly in Mfn2 KO platelets. Furthermore, complex I activity was reduced in Mfn2 KO platelets compared to WT platelets (P&lt;0.01). Both basal and thrombin triggered mitochondrial oxygen consumption rate as assessed by Seahorse analyzer was significantly reduced in Mfn2 KO platelets (1.28 pmol/min/µg protein) compared to WT control platelets (3.06 pmol/min/µg protein). Platelet activation was subtly, yet significantly, decreased in Mfn2 KO platelets compared to WT platelets as assessed by surface expression of activated integrin alpha2b/beta3 and P-selectin. In addition, Mfn2 KO platelets had impaired Ca 2+ signaling, ROS generation, and procoagulant platelet formation (PS +ve platelets), and formed fewer platelet-neutrophil aggregates (PNAs) compared to WT platelets (P=0.01). Consistent with this, we observed significantly prolonged bleeding times in Mfn2 KO mice compared to their WT control littermates (P=0.001). Finally, mice with loss of platelet Mfn2 exhibited a modest reduction in ischemic stroke infarct size after cerebral ischemia-reperfusion that was statistically significant (P&lt;0.01). Taken together these results suggest that MFN2 preserves mitochondrial functions necessary for platelet survival and activity, and that loss of MFN2 leads to accelerated platelet death, dysfunction, and altered hemostasis and thrombosis. Disclosures Rondina: Novartis: Research Funding; Platelet Biogenesis: Membership on an entity's Board of Directors or advisory committees; Acticor Biotech: Membership on an entity's Board of Directors or advisory committees; Platelet Transcriptomics: Patents & Royalties.

Abstract P311: Blocking Succinate Release Enhances Mitochondrial Reactive Oxygen Species Generation And Worsens Ischemia-reperfusion Injury

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Alexander S Milliken ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Ros Generation ◽  
Ros Production ◽  
Succinate Oxidation ◽  
Fluorescence Measurements ◽  
Mitochondrial Ros ◽  
The Impact ◽  
Infarction Heart

Succinate is a metabolite that plays a central role in ischemia-reperfusion (IR) injury,which is relevant to myocardial infarction (heart attack) and stroke. Succinateaccumulates during ischemia and is rapidly consumed at reperfusion driving reactiveoxygen species (ROS) generation at complex-I (Cx-I) and III of the mitochondrial electrontransport chain. This ROS production triggers cell-death, leading to tissue necrosis.Although succinate oxidation has been extensively studied and exploited as a noveltherapeutic target, only 1/3 of the succinate accumulated in ischemia is oxidized atreperfusion, with the remaining 2/3 being released from the cell via monocarboxylatetransporter 1 (MCT1). Extracellular succinate is thought to be pro-inflammatory, and ithas been proposed that preventing succinate release may be therapeutically beneficial.To determine the impact of preventing succinate release on IR injury, we comparedfunctional recovery (i.e. rate x pressure product, RPP) and infarction (i.e. tissue necrosis)of Langendorff perfused mouse hearts treated with an MCT1 inhibitor, AR-C155858,versus vehicle control. This revealed that succinate retention worsens IR injury (i.e.increased infarction and decreased functional recovery) likely due to increased ROS. Totest this hypothesis, we utilized a Langendorff apparatus positioned within aspectrofluorimeter, which permits real-time fluorescence measurements in beatingmouse hearts. Using the mitochondria targeted superoxide probe, MitoSOX red tomeasure ROS production at reperfusion + AR-C155858, demonstrated that succinateretention leads to enhanced mitochondrial ROS generation at the onset of reperfusion.Overall, these results suggest that inhibiting succinate release in the context of IR injurymay not be a viable therapeutic approach, regardless of any downstream anti-inflammatory effects.

scholarly journals Beclin 1/Bcl-2 complex-dependent autophagy activity modulates renal susceptibility to ischemia-reperfusion injury and mediates renoprotection by Klotho

2020 ◽  
Vol 318 (3) ◽  
pp. F772-F792 ◽  
Author(s):  
Peng Li ◽  
Mingjun Shi ◽  
Jenny Maique ◽  
Joy Shaffer ◽  
Shirley Yan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Genetic Manipulation ◽  
Protein Complexes ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Beclin 1 ◽  
Klotho Protein ◽  
And Function ◽  
Autophagy Activity

Klotho- and beclin 1-driven autophagy extends life. We examined the role of beclin 1 in modifying acute kidney injury (AKI) and whether beclin 1 mediates Klotho’s known renoprotective action in AKI. AKI was induced by ischemia-reperfusion injury in mice with different levels of autophagy activity by genetic manipulation: wild-type (WT) mice with normal beclin 1 expression and function, mice with normal beclin 1 levels but high activity through knockin of gain-of-function mutant beclin 1 ( Becn1F121A), mice with low beclin 1 levels and activity caused by heterozygous global deletion of beclin 1 ( Becn1+/−), or mice with extremely low beclin 1 activity from knockin of the mutant constitutively active beclin 1 inhibitor Bcl-2 ( Bcl2AAA). Klotho was increased by transgenic overexpression ( Tg-Kl) or recombinant Klotho protein administration. After ischemia-reperfusion injury, Becn1F121A mice (high autophagy) had milder AKI and Becn1+/− and Bcl2AAA mice (low autophagy) had more severe AKI than WT mice. Tg-Kl mice had milder AKI, but its renoprotection was partially attenuated in Becn1+/− ;Tg-Kl mice and was significantly reduced, although not completely abolished, in Bcl2AAA;Tg-Kl mice. Recombinant Klotho protein conferred more renoprotection from AKI in WT mice than in Becn1+/− or Bcl2AAA mice. Klotho reduced beclin 1/Bcl-2 protein complexes and increased autophagy activity, but this effect was less prominent in mice or cells with Bcl2AAA. Transfected Bcl2AAA or Becn1F123A decreased or increased autophagy activity and rendered cells more susceptible or more resistant to oxidative cytotoxicity, respectively. In conclusion, beclin 1 confers renoprotection by activating autophagy. Klotho protects the kidney partially via disruption of beclin 1/Bcl-2 interactions and enhancement of autophagy activity.

Sign in / Sign up

Export Citation Format

Share Document