bims-mikwok 2023-09-03 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–09–03
seven papers selected by
Gavin McStay, Liverpool John Moores University

Mitophagy-promoting agents and their ability to promote healthy-aging.
Ruscogenin Alleviates Myocardial Ischemia via Myosin IIA-Dependent Mitochondrial Fusion and Fission Balance.
Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.
Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
NEDD4 activates mitophagy by interacting with LC3 to restrain reactive oxygen species and apoptosis in Apostichopus japonicus challenged with Vibrio splendidus.
Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.
Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1.

Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]

Mitophagy-promoting agents and their ability to promote healthy-aging.

Vijigisha Srivastava, Einav Gross.

  The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.1042/BST20221363
Am J Chin Med. 2023 Aug 31. 1-26

Ruscogenin Alleviates Myocardial Ischemia via Myosin IIA-Dependent Mitochondrial Fusion and Fission Balance.

Jin-Cheng Liu, Qing-Fei Zhao, Ling Zhang, Bo-Yang Yu, Fang Li, Jun-Ping Kou.

  Ruscogenin (RUS), a major effective steroidal sapogenin derived from Ophiopogon japonicas, has been reported to alleviate myocardial ischemia (MI), but its cardioprotective mechanism is still not completely clear. In this study, we observed that RUS markedly reduced MI-induced myocardial injury, as evidenced by notable reductions in infarct size, improvement in biochemical markers, alleviation of cardiac pathology, amelioration of mitochondrial damage, and inhibition of myocardial apoptosis. Moreover, RUS notably suppressed oxygen-glucose deprivation (OGD)-triggered cell injury and apoptosis. Notably, RUS demonstrated a considerable decrease of the interaction between myosin IIA and F-actin, along with the restoration of mitochondrial fusion and fission balance. We further confirmed that the effects of RUS on MI were mediated by myosin IIA using siRNA and overexpression techniques. The inhibition of myosin IIA resulted in a significant improvement of mitochondrial fusion and fission imbalance, while simultaneously counteracting the beneficial effects of RUS. By contrast, overexpression of myosin IIA aggravated the imbalance between mitochondrial fusion and fission and partially weakened the protection of RUS. These findings suggest that myosin IIA is essential or even a key functional protein in the cardioprotection of RUS. Overall, our results have elucidated an undiscovered mechanism involving myosin IIA-dependent mitochondrial fusion and fission balance for treating MI. Furthermore, our study has uncovered a novel mechanism underlying the protective effects of RUS.

Keywords:  Apoptosis; Mitochondrial Fission; Mitochondrial Fusion; Myocardial Ischemia; Myosin IIA; Ruscogenin

DOI:  https://doi.org/10.1142/S0192415X23500830
Adv Microbiol. 2023 Aug;13(8): 399-419

Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.

Robin L Holland, Kristopher D Bosi, Ami Y Seeger, Steven R Blanke.

  The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.

Keywords:  ATP; Helicobacter pylori; VacA; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission; mitochondrial transmembrane potential; oxidative phosphorylation; vacuolating cytotoxin

DOI:  https://doi.org/10.4236/aim.2023.138026
Commun Biol. 2023 08 29. 6(1): 889

Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.

Lianjiu Su, Jiahao Zhang, Jing Wang, Xiaozhan Wang, Edward Cao, Chen Yang, Qihao Sun, Ramadoss Sivakumar, Zhiyong Peng.

Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.

DOI: https://doi.org/10.1038/s42003-023-05226-x
Fish Shellfish Immunol. 2023 Aug 26. pii: S1050-4648(23)00523-5. [Epub ahead of print] 109037

NEDD4 activates mitophagy by interacting with LC3 to restrain reactive oxygen species and apoptosis in Apostichopus japonicus challenged with Vibrio splendidus.

Yangxi Xiang, Xuemei Duan, Yina Shao, Lianlian Sun.

  Mitophagy, the selective degradation of damaged mitochondria by autophagy, plays a crucial role in the survival of coelomocytes in Apostichopus japonicus following Vibrio splendidus infection by suppressing the generation of reactive oxygen species (ROS) and attenuating cell apoptosis. A recent study revealed that reducing the expression of the neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4), an enzyme 3 (E3) ubiquitin ligase, significantly affects mitochondrial degradation. Prior to the present study, the functional role of NEDD4 in marine invertebrates was largely unexplored. Therefore, we investigated the role of NEDD4 in the activation of mitophagy, modulation of ROS levels, and induction of apoptosis in A. japonicus infected with V. splendidus. The results demonstrated that V. splendidus infection and lipopolysaccharide (LPS) challenge significantly increased the mRNA levels of NEDD4 in A. japonicus coelomocytes, which was consistent with changes in mitophagy under the same conditions. Knockdown of AjNEDD4 using specific small interfering RNAs (siRNAs) impaired mitophagy and caused accumulation of damaged mitochondria, as observed using transmission electron microscopy (TEM) and confocal microscopy. Furthermore, AjNEDD4 was localized to the mitochondria in both coelomocytes and HEK293T cells. Simultaneously, coelomocytes were treated with the inhibitor indole-3-carbinol (I3C) to confirm the regulatory role of AjNEDD4 in mitophagy. The accumulation of AjNEDD4 in the mitochondria and the level of mitophagy decreased. Subsequent investigations demonstrated that AjNEDD4 interacts directly with the microtubule-associated protein light chain 3 (LC3), a key regulator of autophagy and mitophagy, indicating its involvement in the mitophagy pathway. Moreover, AjNEDD4 interference hindered the interaction between AjNEDD4 and LC3, thereby impairing the engulfment and subsequent clearance of damaged mitochondria. Finally, AjNEDD4 interference led to a significant increase in intracellular ROS levels, followed by increased apoptosis. Collectively, these findings suggest that NEDD4 acts as a crucial regulator of mitophagy in A. japonicus and plays a vital role in maintaining cellular homeostasis following V. splendidus infection. NEDD4 suppresses ROS production and subsequent apoptosis by promoting mitophagy, thereby safeguarding the survival of A. japonicus under pathogenic conditions. Further investigation of the mechanisms underlying NEDD4-mediated mitophagy may provide valuable insights into the development of novel strategies for disease control in aquaculture farms.

Keywords:  Apostichopus japonicus; Microtubule-associated protein 1 light chain 3; Mitophagy; Neural precursor cell-expressed developmentally downregulated gene 4; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.fsi.2023.109037
Ecotoxicol Environ Saf. 2023 Aug 28. pii: S0147-6513(23)00913-2. [Epub ahead of print]264 115409

Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.

Shulin Shan, Zhidan Liu, Shuai Wang, Zhaoxiong Liu, Shihua Chao, Cuiqin Zhang, Ming Li, Fuyong Song.

  Carbon tetrachloride (CCl4)-mediated liver damage has been well recognized, but the sources and mechanisms of mitochondrial damage during this progress still remain poorly understood. Accumulating evidence has revealed that LonP1-TDP-43 pathway affect proper mitochondrial integrity and function in neurodegenerative diseases. The current study aims to investigate whether mitochondrial oxidative stress regulate LonP1-TDP-43 pathway and the possible roles of this pathway in CCl4-driven liver fibrosis. We found that TDP-43 interacted with LonP1 in chronic CCl4 exposure-induced hepatic fibrogenesis. Moreover, CCl4 led to deficiency of LonP1 and excessive accumulation of TDP-43 on mitochondria. Particularly, the gene correlation analysis for liver fibrosis patients RNA sequencing (RNA-seq) results (GSE159676) showed an obvious negative correlation between LonP1 and TDP-43. By contrast, MitoQ enhanced the occurrence of mitochondrial unfolded protein response (mtUPR), especially the activation of LonP1 after CCl4 treatment. Importantly, mitochondrial antioxidant also promoted the degradation of TDP-43 and alleviated mitochondrial damage. In addition, our results showed that CCl4 induced the release of mitochondrial DNA (mtDNA) and effectively elevated cGAS-STING-mediated immune response, which can be inhibited by MitoQ. Finally, MitoQ prevented CCl4-induced liver fibrosis. Together, our study revealed that LonP1-TDP-43 pathway mediated by mitochondrial oxidative stress participated in the progress of CCl4-drived liver fibrosis. Therefore, mitigating or reversing mitochondrial damage through targeting LonP1-TDP-43 pathway may serve as a promising therapeutic strategy for CCl4 exposure-induced liver diseases.

Keywords:  Liver fibrosis; LonP1; Mitochondrial dysfunction; TDP-43

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115409
Mol Cancer Ther. 2023 Aug 30.

Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1.

Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Scott D Slattery, Andy Anantha, Alan Cooper, Mark Hannink, Axel Schambach, Anneke Doerrie, Alexey Kotylarov, Matthias Gaestel, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, David M Weinstock, Marc Liesa, Matthew J Kostura.

DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation and accumulation of misfolded proteins. Here we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, that activate the ISR through the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal-center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first- of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.

DOI: https://doi.org/10.1158/1535-7163.MCT-22-0718