bims-mecmid 2021-11-21 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2021–11–21
seven papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Targeting protein interaction networks in mitochondria dynamics for cancer therapy.
P2RY2 alleviates cerebral ischemia-reperfusion injury by inhibiting YAP phosphorylation and reducing mitochondrial fission.
Emodin prevents renal ischemia-reperfusion injury via suppression of CAMKII/DRP1-mediated mitochondrial fission.
Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy.
Widespread use of unconventional targeting signals in mitochondrial ribosome proteins.
Normothermic machine perfusion attenuates hepatic ischaemia-reperfusion injury by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.

Drug Discov Today. 2021 Nov 10. pii: S1359-6446(21)00485-2. [Epub ahead of print]

Targeting protein interaction networks in mitochondria dynamics for cancer therapy.

Chieh-Fan Yin, Yi-Wen Chang, Hsuan-Cheng Huang, Hsueh-Fen Juan.

  Mitochondria are crucial organelles that provide energy via oxidative phosphorylation in eukaryotic cells and also have critical roles in growth, division, and the cell cycle, as well as the rapid adaptation required to meet the metabolic needs of the cell. Mitochondrial processes are highly dynamic; fusion and fission can vary with cell type, cellular context, and stress levels. Accumulating evidence demonstrates that an imbalance in mitochondrial dynamics leads to death in numerous types of human cancer cells. Therefore, modulating mitochondrial dynamics could be a therapeutic target. In this review, we provide an overview of the protein interaction networks involved in mitochondrial dynamics as effective and feasible drug targets and discuss the related potential therapeutic strategies for cancer.

Keywords:  Cancer therapy; Mitochondria dynamics; Mitochondrial fission; Mitochondrial fusion; Protein-protein interaction network

DOI:  https://doi.org/10.1016/j.drudis.2021.11.006
Neuroscience. 2021 Nov 12. pii: S0306-4522(21)00572-8. [Epub ahead of print]

P2RY2 alleviates cerebral ischemia-reperfusion injury by inhibiting YAP phosphorylation and reducing mitochondrial fission.

Long-Xing Xue, Song-Feng Chen, Shi-Xing Xue, Xin-Zhong Zhang, Ya-Jun Lian.

  P2Y purinoceptor 2 (P2RY2) is involved in the regulation of cell proliferation and apoptosis. The aim of this study was to explore the effects of P2RY2 on cerebral ischemia/reperfusion (I/R) injury and its molecular mechanism. Middle cerebral artery occlusion (MCAO) model in rats and OXYGEN and oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells were established. P2RY2 expressions in I/R injury model in vitro and in vivo were up-regulated. In the OGD/R group, ROS level, cyto-CytC and mitochondrial fission factors expressions and cell apoptosis were increased, while SOD activity, mito-CytC and mitochondrial fusion factors expressions were decreased. P2RY2 overexpression could reverse these results. Up-regulated P2RY2 expression decreased Yes-associated protein (YAP) phosphorylation level, promote the nuclear translocation of YAP, and inhibit cell apoptosis, which can be reversed by YAP inhibitor verteporfin. The addition of PI3K/AKT inhibitor LY294002 could reverse the decrease of YAP phosphorylation level and cell apoptosis, and the increase of nuclear translocation caused by P2RY2 overexpression. Further in vivo studies validated that interference with P2RY2 increased the cerebral infarction area, decreased AKT expression, enhanced YAP phosphorylation, and inhibited the nuclear translocation of YAP. In conclusion, P2RY2 can alleviate cerebral I/R injury by inhibiting YAP phosphorylation and reducing mitochondrial fission.

Keywords:  P2RY2; PI3K/AKT; YAP; cerebral ischemia-reperfusion injury; mitochondrial fission

DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.013
Eur J Pharmacol. 2021 Nov 15. pii: S0014-2999(21)00759-7. [Epub ahead of print] 174603

Emodin prevents renal ischemia-reperfusion injury via suppression of CAMKII/DRP1-mediated mitochondrial fission.

Yanqing Wang, Qian Liu, Jiaying Cai, Pin Wu, Di Wang, Yundi Shi, Tianru Huyan, Jing Su, Xuejun Li, Qi Wang, Hong Wang, Fengxue Zhang, Ok-Nam Bae, Lu Tie.

  Acute kidney injury (AKI) is a serious threat to human health. Clinically, ischemia-reperfusion (I/R) injury is considered one of the most common contributors to AKI. Emodin has been reported to alleviate I/R injury in the heart, brain, and small intestine in rats and mice through its anti-inflammatory effects. The present study investigated whether emodin improves AKI induced by I/R and elucidate the molecular mechanisms. We used a mouse model of renal I/R injury and human renal tubular epithelial cell model of hypoxia/reoxygenation (H/R) injury. Ischemia/reperfusion resulted in renal dysfunction. Pretreatment with emodin ameliorated renal injury in mice following I/R injury. Emodin reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial reactive oxygen species and accelerated the recovery of adenosine triphosphate both in vivo and in vitro. Emodin prevented mitochondrial fission and restored the balance of mitochondrial dynamics. The phosphorylation of dynamin-related protein 1 (DRP1) at Ser616, a master regulator of mitochondrial fission, was upregulated in both models of I/R and H/R injury, and this upregulation was blocked by emodin. Using computational cognate protein kinase prediction and specific kinase inhibitors, we found that emodin inhibited the phosphorylation of calcium/calmodulin-dependent protein kinase II (https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1554), thereby inhibiting its kinase activity and reducing the phosphorylation of DRP1 at Ser616. The results demonstrated that emodin pretreatment could protect renal function by improving mitochondrial dysfunction induced by I/R.

Keywords:  Acute kidney injury; Emodin; Mitochondrion; ROS

DOI:  https://doi.org/10.1016/j.ejphar.2021.174603
Autophagy. 2021 Nov 15. 1-3

Beyond mitophagy: mitochondrial-derived vesicles can get the job done!

Payel Mondal, Christina Towers.

  Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.

Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy

DOI:  https://doi.org/10.1080/15548627.2021.1999562
Oxid Med Cell Longev. 2021 ;2021 9265016

SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy.

Tianyi Ma, Xiaohui Huang, Haoxiao Zheng, Guolin Huang, Weiwen Li, Xinyue Liu, Jingjing Liang, Yue Cao, Yunzhao Hu, Yuli Huang.

Background: The mitochondrial dynamics and mitochondrial biogenesis are essential for maintaining the bioenergy function of mitochondria in diabetic cardiomyopathy (DCM). Previous studies have revealed that secreted frizzled-related protein 2 (SFRP2) is beneficial against apoptosis and oxidative stress. However, no research has confirmed whether SFRP2 regulates oxidative stress and apoptosis through mitochondrial function in DCM.
Methods: Exposure of H9C2 cardiomyocytes in high glucose (HG) 25 mM and palmitic acid (PAL) 0.2 mM was used to simulate DCM in vitro. H9C2 cells with SFRP2 overexpression or SFRP2 knockdown were constructed and cultured under glucolipotoxicity or normal glucose conditions. An SD rat model of type 2 diabetes mellitus (T2DM) was generated using a high-fat diet combined with a low-dose STZ injection. Overexpression of SFRP2 in the rat model was generated by using an adeno-associated virus approach. CCK-8, TUNEL assay, and DHE staining were used to detect cell viability, and MitoTracker Red CMXRos was used to detect changes in mitochondrial membrane potential. We used qRT-PCR and western blot to further explore the mechanisms of SFRP2 regulating mitochondrial dynamics through the AMPK/PGC1-α pathway to improve diabetic cardiomyocyte injury.
Results: Our results indicated that SFRP2 was significantly downregulated in H9C2 cells and cardiac tissues in T2DM conditions, accompanied by decreased expression of mitochondrial dysfunction. The mitochondrial membrane potential was reduced, and the cells were led to oxidative stress injury and apoptosis. Furthermore, the overexpression of SFRP2 could reverse apoptosis and promote mitochondrial function in T2DM conditions in vitro and in vivo. We also found that silencing endogenous SFRP2 could further promote glucolipotoxicity-induced mitochondrial dysfunction and apoptosis in cardiomyocytes, accompanied by downregulation of p-AMPK.
Conclusion: SFRP2 exerted cardioprotective effects by salvaging mitochondrial function in an AMPK-PGC1-α-dependent manner, which modulates mitochondrial dynamics and mitochondrial biogenesis, reducing oxidative stress and apoptosis. SFRP2 may be a promising therapeutic biomarker in DCM.

DOI: https://doi.org/10.1155/2021/9265016
EMBO J. 2021 Nov 17. e109519

Widespread use of unconventional targeting signals in mitochondrial ribosome proteins.

Yury S Bykov, Tamara Flohr, Felix Boos, Naama Zung, Johannes M Herrmann, Maya Schuldiner.

  Mitochondrial ribosomes are complex molecular machines indispensable for respiration. Their assembly involves the import of several dozens of mitochondrial ribosomal proteins (MRPs), encoded in the nuclear genome, into the mitochondrial matrix. Proteomic and structural data as well as computational predictions indicate that up to 25% of yeast MRPs do not have a conventional N-terminal mitochondrial targeting signal (MTS). We experimentally characterized a set of 15 yeast MRPs in vivo and found that five use internal MTSs. Further analysis of a conserved model MRP, Mrp17/bS6m, revealed the identity of the internal targeting signal. Similar to conventional MTS-containing proteins, the internal sequence mediates binding to TOM complexes. The entire sequence of Mrp17 contains positive charges mediating translocation. The fact that these sequence properties could not be reliably predicted by standard methods shows that mitochondrial protein targeting is more versatile than expected. We hypothesize that structural constraints imposed by ribosome assembly interfaces may have disfavored N-terminal presequences and driven the evolution of internal targeting signals in MRPs.

Keywords:  mitochondria; mitochondrial ribosome; mitochondrial targeting signal; targeting; translocation

DOI:  https://doi.org/10.15252/embj.2021109519
J Cell Mol Med. 2021 Nov 16.

Normothermic machine perfusion attenuates hepatic ischaemia-reperfusion injury by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.

Wenyan Liu, Yang Fan, Hongfan Ding, Dan Han, Yang Yan, Rongqian Wu, Yi Lv, Xinglong Zheng.

  Extracellular cold-inducible RNA-binding protein (CIRP) is a proinflammatory mediator that aggravates ischaemia-reperfusion injury (IRI). Normothermic machine perfusion (NMP) could effectively alleviate the IRI of the liver, but the underlying mechanism remains to be explored. We show that human DCD livers secreted a large amount of CIRP during static cold storage (CS), which is released into the circulation after reperfusion. The expression of CIRP was related to postoperative IL-6 levels and liver function. In a rat model, the CIRP expression was upregulated during warm ischaemia and cold storage. Then, rat DCD livers were preserved using CS, hypothermic oxygenated machine perfusion (HOPE) and NMP. C23, a CIRP inhibitor, was administrated in the HOPE group. Compared with CS, NMP significantly inhibited CIRP expression and decreased oxidative stress by downregulating NADPH oxidase and upregulating UCP2. NMP markedly inhibited the mitochondrial fission-related proteins Drp-1 and Fis-1. Further, NMP increased the mitochondrial biogenesis-related protein, TFAM. NMP significantly reduced inflammatory reactions and apoptosis after reperfusion, and NMP-preserved liver tissue had higher bile secretion and ICG metabolism compared to the CS group. Moreover, C23 administration attenuated IRI in the HOPE group. Additionally, HL-7702 cells were stimulated with rhCIRP and C23. High rhCIRP levels increased oxidative stress and apoptosis. In summary, NMP attenuates the IRI of DCD liver by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.

Keywords:  CIRP; ischaemia-reperfusion injury; mitochondrial fission; oxidative stress

DOI:  https://doi.org/10.1111/jcmm.17062