bims-mikwok 2024-05-12 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–05–12
fiveteen papers selected by
Gavin McStay, Liverpool John Moores University

An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt.
A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.
Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.
Ruthenium Red Alleviates Post-Resuscitation Myocardial Dysfunction by Upregulating Mitophagy through Inhibition of USP33 in a Cardiac Arrest Rat Model.
A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer.
Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice.
Modulating Synovial Macrophage Pyroptosis and Mitophagy Interactions to Mitigate Osteoarthritis Progression using Functionalized Nanoparticles.
Melatonin attenuates renal ischemia-reperfusion injury by regulating mitochondrial dynamics and autophagy through AMPK/DRP1.
ROS-mediated NRF2/p-ERK1/2 signaling-involved mitophagy contributes to macrophages activation induced by CdTe quantum dots.
MicroRNA-142-3p alleviated high salt-induced cardiac fibrosis via downregulating optineurin-mediated mitophagy.
USP7 cardiomyocyte specific knockout causes disordered mitochondrial biogenesis and dynamics and early neonatal lethality in mice.
Mitophagy-regulated Necroptosis plays a vital role in the nephrotoxicity of Fumonisin B1 in vivo and in vitro.

Nat Commun. 2024 May 07. 15(1): 3793

An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.

Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.

Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.

DOI: https://doi.org/10.1038/s41467-024-48189-1
J Cell Signal. 2023 ;4(4): 151-162

Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt.

Chin-Wen Wei, Thomas Lerdall, Fatimah Najjar, Li-Na Wei.

  Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1. Here we uncovered that mitochondrial DNA (mtDNA) content and the expression of genes involved in respiration were significantly reduced in CKO mouse spinal cord, accompanied by significantly elevated reactive oxygen species (ROS) and unfolded protein load, indicating that CRABP1 deficiency caused mitochondrial dysfunction. Further analyses of spinal cord tissues revealed significant reduction in the expression and activity of superoxide dismutase 2 (SOD2), as well as defected mitochondrial unfolded protein response (UPRmt) pathway, specifically an increase in ATF5 mRNA but not its protein level, which suggested failure in the translational response of ATF5 in CKO. Consistently, eukaryotic initiation factor-2α, (eIF2α) phosphorylation was reduced in CKO spinal cord. In a CRABP1 knockdown MN1 model, siCrabp1-MN1, we validated the cell-autonomous function of CRABP1 in modulating the execution of UPRmt. This study reveals a new functional role for CRABP1 in the execution of mitochondrial stress response, that CRABP1 modulates eIF2α phosphorylation thereby contributing to ATF5 translational response that is needed to mitigate mitochondria stress.

Keywords:  Crabp1; Reactive oxygen species; Unfolded protein response; eIF2α

DOI:  https://doi.org/10.33696/signaling.4.102
J Cell Biol. 2024 Jul 01. pii: e202309015. [Epub ahead of print]223(7):

A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.

Dan A Tudorica, Bishal Basak, Alexia S Puerta Cordova, Grace Khuu, Kevin Rose, Michael Lazarou, Erika L F Holzbaur, James H Hurley.

Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.

DOI: https://doi.org/10.1083/jcb.202309015
FASEB J. 2024 May 15. 38(9): e23654

Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.

Man Xu, Li-Peng Li, Xi He, Xing-Zhu Lu, Xue-Yuan Bi, Qi Li, Xiao-Rong Xue.

  Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.

Keywords:  cardiac remodeling; heat shock factor 1; hypertension; metformin; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1096/fj.202400070R
Eur J Pharmacol. 2024 May 02. pii: S0014-2999(24)00321-2. [Epub ahead of print] 176633

Ruthenium Red Alleviates Post-Resuscitation Myocardial Dysfunction by Upregulating Mitophagy through Inhibition of USP33 in a Cardiac Arrest Rat Model.

Fan Zhang, Zhou Ye, Yingqi Ran, Cong Liu, Mingtao Zhang, Xiangchang Xu, Fengqing Song, Lan Yao.

  Cardiac arrest (CA) remains a leading cause of death, with suboptimal survival rates despite efforts involving cardiopulmonary resuscitation and advanced life-support technology. Post-resuscitation myocardial dysfunction (PRMD) is an important determinant of patient outcomes. Myocardial ischemia/reperfusion injury underlies this dysfunction. Previous reports have shown that ruthenium red (RR) has a protective effect against cardiac ischemia-reperfusion injury; however, its precise mechanism of action in PRMD remains unclear. This study investigated the effects of RR on PRMD and analyzed its underlying mechanisms. Ventricular fibrillation was induced in rats, which were then subjected to cardiopulmonary resuscitation to establish an experimental CA model. At the onset of return of spontaneous circulation, RR (2.5 mg/kg) was administered intraperitoneally. Our study showed that RR improved myocardial function and reduced the production of oxidative stress markers such as malondialdehyde (MDA), glutathione peroxidase (GSSG), and reactive oxygen species (ROS) production. RR also helped maintain mitochondrial structure and increased ATP and GTP levels. Additionally, RR effectively attenuated myocardial apoptosis. Furthermore, we observed downregulation of proteins closely related to mitophagy, including ubiquitin-specific protease 33 (USP33) and P62, whereas LC3B (microtubule-associated protein light chain 3B) was upregulated. The upregulation of mitophagy may play a critical role in reducing myocardial injury. These results demonstrate that RR may attenuate PRMD by promoting mitophagy through the inhibition of USP33. These effects are likely mediated through diverse mechanisms, including antioxidant activity, apoptosis suppression, and preservation of mitochondrial integrity and energy metabolism. Consequently, RR has emerged as a promising therapeutic approach for addressing post-resuscitation myocardial dysfunction.

Keywords:  Mitophagy; PINK1/Parkin signaling pathway; Post-resuscitation myocardial dysfunction; Ruthenium red; Ubiquitin-specific protease 33

DOI:  https://doi.org/10.1016/j.ejphar.2024.176633
J Clin Invest. 2024 May 07. pii: e175619. [Epub ahead of print]

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan M Morrow, Kevin A Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.

  Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

Keywords:  Autophagy; Hematology; Leukemias; Mitochondria; Oncology

DOI:  https://doi.org/10.1172/JCI175619
bioRxiv. 2024 Apr 23. pii: 2023.06.25.546449. [Epub ahead of print]

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan Morrow, Kevin Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2 P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2 P95H -induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2 P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2 P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2 P95H mutant MDS and AML.

DOI: https://doi.org/10.1101/2023.06.25.546449
Am J Cancer Res. 2024 ;14(4): 1935-1946

Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer.

Ming-Ming Zhao, Bo Wang, Wen-Xi Huang, Li Zhang, Rui Peng, Chao Wang.

  Endometrial cancer (EC) is a malignancy that poses a threat to woman's health worldwide. Building upon prior work, we explored the inhibitory effect of verteporfin on EC. We showed that verteporfin can damage the mitochondria of EC cells, leading to a decrease of mitochondrial membrane potential and an increase in ROS (reactive oxygen species). In addition, verteporfin treatment was shown to inhibit the proliferation and migration of EC cells, promote apoptosis, and reduce the expression of mitophagy-related proteins PINK1/parkin and TOM20. The ROS inhibitor N-Acetyl Cysteine was able to rescue the expression of PINK1/parkin proteins. This suggests that verteporfin may inhibit mitophagy by elevating ROS levels, thereby inhibiting EC cell viability. The effect of verteporfin on mitophagy supports further investigation as a potential therapeutic option for EC.

Keywords:  Endometrial cancer; PINK1/parkin pathway; mitophagy; verteporfin

DOI:  https://doi.org/10.62347/PMYV3832
Front Mol Biosci. 2024 ;11 1397565

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice.

Lucia Cilenti, Jacopo Di Gregorio, Rohit Mahar, Fei Liu, Camilla T Ambivero, Muthu Periasamy, Matthew E Merritt, Antonis S Zervos.

  Obesity is a growing epidemic affecting millions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(-/-) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases.

Keywords:  MUL1; SCD1; lipogenesis; mitophagy; obesity

DOI:  https://doi.org/10.3389/fmolb.2024.1397565
Acta Biomater. 2024 May 08. pii: S1742-7061(24)00249-6. [Epub ahead of print]

Modulating Synovial Macrophage Pyroptosis and Mitophagy Interactions to Mitigate Osteoarthritis Progression using Functionalized Nanoparticles.

Weizhong Qi, Li Jin, Shiqian Huang, Alafate Aikebaier, Song Xue, QianYi Wang, Qiyue Chen, Yao Lu, Changhai Ding.

  Synovial macrophages play an important role in the progression of osteoarthritis (OA). In this study, we noted that synovial macrophages can activate pyroptosis in a gasdermin D-dependent manner and produce reactive oxygen species (ROS), aberrantly activating the mammalian target of rapamycin complex 1 (mTORC1) pathway and matrix metalloproteinase-9 (MMP9) expression in synovial tissue samples collected from both patients with OA and collagen-induced osteoarthritis (CIOA) mouse model. To overcome this, we constructed rapamycin- (RAPA, a mTORC1 inhibitor) loaded mesoporous Prussian blue nanoparticles (MPB NPs, for catalyzing ROS) and modified the NPs with MMP9-targeted peptides (favor macrophage targeting) to develop RAPA@MPB-MMP9 NPs. The inherent enzyme-like activity and RAPA released from RAPA@MPB-MMP9 NPs synergistically impeded the pyroptosis of macrophages and the activation of the mTORC1 pathway. In particular, the NPs decreased pyroptosis-mediated ROS generation, thereby inhibiting cGAS-STING signaling pathway activation caused by the release of mitochondrial DNA. Moreover, the NPs promoted macrophage mitophagy to restore mitochondrial stability, alleviate pyroptosis-related inflammatory responses, and decrease senescent synoviocytes. After the as-prepared NPs were intra-articularly injected into the CIOA mouse model, they efficiently attenuated synovial macrophage pyroptosis and cartilage degradation. In conclusion, our study findings provide a novel therapeutic strategy for OA that modulates the pyroptosis and mitophagy of synovial macrophage by utilizing functionalized NPs. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) presents a significant global challenge owing to its complex pathogenesis and finite treatment options. Synovial macrophages have emerged as key players in the progression of OA, managing inflammation and tissue destruction. In this study, we discovered a novel therapeutic strategy in which the pyroptosis and mitophagy of synovial macrophages are targeted to mitigate OA pathology. For this, we designed and prepared rapamycin-loaded mesoporous Prussian blue nanoparticles (RAPA@MPB-MMP9 NPs) to specifically target synovial macrophages and modulate their inflammatory responses. These NPs could efficiently suppress macrophage pyroptosis, diminish reactive oxygen species production, and promote mitophagy, thereby alleviating inflammation and protecting cartilage integrity. Our study findings not only clarify the intricate mechanisms underlying OA pathogenesis but also present a promising therapeutic approach for effectively managing OA by targeting dysregulation in synovial macrophages.

Keywords:  Osteoarthritis; Prussian blue nanoparticles; mitophagy; pyroptosis; synovial macrophages

DOI:  https://doi.org/10.1016/j.actbio.2024.05.014
Shock. 2024 Apr 26.

Melatonin attenuates renal ischemia-reperfusion injury by regulating mitochondrial dynamics and autophagy through AMPK/DRP1.

Huabin Wang, Yi Li, Xichao Cao, Heping Niu, Xiaoran Li, Jirong Wang, Jianwei Yang, Changhong Xu, Hailong Wang, Shun Wan, Kunpeng Li, Shengjun Fu, Li Yang.

ABSTRACT: Ischemia-reperfusion injury (IRI) often stems from an imbalance between mitochondrial dynamics and autophagy. Melatonin mitigates IRI by regulating mitochondrial dynamics. However, the precise molecular mechanism underlying the role of melatonin in reducing IRI through modulating mitochondrial dynamics remains elusive. The objective of this study was to investigate whether pre-treatment with melatonin before IRI confers protective effects by modulating mitochondrial dynamics and mitophagy. Melatonin pre-treatment was administered to HK-2 cells and live rats before subjecting them to hypoxia-reoxygenation (HR) or IRI, respectively. Cells and rat kindey models were evaluated for markers of oxidative stress, autophagy, mitochondrial dynamics, and the expression of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and phospho-AMPKα (P-AMPK). Following renal IRI, increased mitochondrial fission and autophagy were observed, accompanied by exacerbated cellular oxidative stress injury and aggravated mitochondrial dysfunction. Nevertheless, melatonin pre-treatment inhibited mitochondrial fission, promoted mitochondrial fusion, and attenuated autophagy levels. This intervention was correlated with a notable reduction in oxidative stress injury and remarkable restoration of mitochondrial functionality. IRI led to a decline in P-AMPK levels, whereas melatonin pre-treatment increased the level of P-AMPK levels. Silencing AMPK with small interfering RNA exacerbated mitochondrial damage, and in this context, melatonin pre-treatment did not alleviate mitochondrial fission or autophagy levels but resulted in sustained oxidative stress damage. Collectively, these findings indicate that melatonin pre-treatment shields the kidneys from IRI by mitigating excessive mitochondrial fission, moderating autophagy levels, and preserving appropriate mitochondrial fission, all in an AMPK-dependent manner.

DOI: https://doi.org/10.1097/SHK.0000000000002330
Toxicology. 2024 May 04. pii: S0300-483X(24)00106-9. [Epub ahead of print] 153825

ROS-mediated NRF2/p-ERK1/2 signaling-involved mitophagy contributes to macrophages activation induced by CdTe quantum dots.

Na Liu, Ying Liang, Tingting Wei, Xiaoquan Huang, Ting Zhang, Meng Tang.

  Cadmium telluride (CdTe) quantum dots (QDs) have garnered significant attention for tumor imaging due to their exceptional properties. However, there remains a need for further investigation into their potential toxicity mechanisms and corresponding enhancements. Herein, CdTe QDs were observed to accumulate in mouse liver, leading to a remarkable overproduction of IL-1β and IL-6. Additionally, there was evidence of macrophage infiltration and activation following exposure to 12.5 μmol/kg body weight of QDs. To elucidate the underlying mechanism of macrophage activation, CdTe QDs functionalized with 3-mercaptopropionic acid (MPA) were utilized. In vitro experiments revealed that 1.0μM MPA-CdTe QDs activated PINK1-dependent mitophagy in RAW264.7 macrophages. Critically, the autophagic flux remained unimpeded, as demonstrated by the absence of p62 accumulation, LC3 turnover assay results, and successful fusion of autophagosomes with lysosomes. Mechanically, QDs increased reactive oxygen species (ROS) and mitoROS by damaging both mitochondria and lysosomes. ROS, in turn, inhibited NRF2, resulting in the phosphorylation of ERK1/2 and subsequent activation of mitophagy. Notably, 1.0μM QDs disrupted lysosomes but autophagic flux was not impaired. Eventually, the involvement of the ROS-NRF2-ERK1/2 pathway-mediated mitophagy in the increase of IL-1β and IL-6 in macrophages was confirmed using Trolox, MitoTEMPO, ML385, specific siRNAs, and lentivirus-based interventions. This study innovatively revealed the pro-inflammatory rather than anti-inflammatory role of mitophagy in nanotoxicology, shedding new light on the mechanisms of mitochondrial disorders induced by QDs and identifying several molecular targets to comprehend the toxicological mechanisms of CdTe QDs.

Keywords:  Macrophage; Mitophagy; NRF2; Quantum dots; ROS

DOI:  https://doi.org/10.1016/j.tox.2024.153825
iScience. 2024 May 17. 27(5): 109764

MicroRNA-142-3p alleviated high salt-induced cardiac fibrosis via downregulating optineurin-mediated mitophagy.

Yong Li, Kun Zhao, Yifang Hu, Fengze Yang, Peng Li, Yun Liu.

  High salt can induce cardiac damage. The aim of this present study was to explore the effect and the mechanism of microRNA (miR)-142-3p on the cardiac fibrosis induced by high salt. Rats received high salt diet to induce cardiac fibrosis in vivo, and neonatal rat cardiac fibroblasts (NRCF) treated with sodium chloride (NaCl) to induce fibrosis in vitro. The fibrosis and mitochondrial autophagy levels were increased the heart and NRCF treated with NaCl, which were alleviated by miR-142-3p upregulation. The fibrosis and mitochondrial autophagy levels were elevated in NRCF after treating with miR-142-3p antagomiR. Optineurin (OPTN) expression was increased in the mitochondria of NRCF induced by NaCl, which was attenuated by miR-142-3p agomiR. OPTN downregulation inhibited the increases of fibrosis and mitochondrial autophagy levels induced by NaCl in NRCF. These results miR-142-3p could alleviate high salt-induced cardiac fibrosis via downregulation of OPTN to reduce mitophagy.

Keywords:  Pathophysiology; cell biology; health sciences; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.109764
Int J Cardiol. 2024 May 07. pii: S0167-5273(24)00771-X. [Epub ahead of print]408 132149

USP7 cardiomyocyte specific knockout causes disordered mitochondrial biogenesis and dynamics and early neonatal lethality in mice.

Meiling Yan, Yu Mei, Tianjun Zhang, Zhou Liu, Liyan Su, Yang Xiao, Xunlong Zhong, Yanjie Lu.

   BACKGROUND: Ubiquitination is an enzymatic modification involving ubiquitin chains, that can be reversed by deubiquitination (DUB) enzymes. Ubiquitin-specific protease 7 (USP7), which is also known as herpes virus-associated ubiquitin-specific protease (HAUSP), has been shown to play a vital role in cardiovascular diseases. However, the underlying molecular mechanism by which USP7 regulates cardiomyocyte function has not been reported.
METHODS: To understand the physiological function of USP7 in the heart, we constructed cardiomyocyte-specific USP7 conditional knockout mice.
RESULTS: We found that homozygous knockout mice died approximately three weeks after birth, while heterozygous knockout mice grew normally into adulthood. Severe cardiac dysfunction, hypertrophy, fibrosis, and cell apoptosis were observed in cardiomyocyte-specific USP7 knockout mice, and these effects were accompanied by disordered mitochondrial dynamics and cardiometabolic-related proteins.
CONCLUSIONS: In summary, we investigated changes in the growth status and cardiac function of cardiomyocyte-specific USP7 knockout mice, and preliminarily explored the underlying mechanism.

Keywords:  Cardiomyocyte-specific knockout mice; Mitochondria homeostasis; PGC1α/PPARα; USP7

DOI:  https://doi.org/10.1016/j.ijcard.2024.132149
Food Chem Toxicol. 2024 May 03. pii: S0278-6915(24)00280-1. [Epub ahead of print] 114714

Mitophagy-regulated Necroptosis plays a vital role in the nephrotoxicity of Fumonisin B1 in vivo and in vitro.

Zhang Ping, Zhang Shuxia, Du Xinyu, Huang Kehe, Chen Xingxiang, Wang Chunfeng.

  Fumonisin B1 (FB1), one of the most widely distributed mycotoxins found in grains and feeds as contaminants, affects many organs including the kidney once ingested. However, the nephrotoxicity of FB1 remains to be further uncovered. The connection between necroptosis and nephrotoxicity of FB1 has been investigated in this study. The results showed that mice exposed to high doses of FB1 (2.25 mg/kg b.w.) developed kidney damage, with significant increases in proinflammatory cytokines (Il-6, Il-1β), kidney injury-related markers (Ngal, Ntn-1), and gene expressions linked to necroptosis (Ripk1, Ripk3, Mlkl). The concentration-dependent damage effects of FB1 on PK-15 cells contain cytotoxicity, cellular inflammatory response, and necroptosis. These FB1-induced effects can be neutralized by pretreatment with the necroptosis inhibitor Nec-1. Additionally, FB1 caused mitochondrial damage and mitophagy in vivo and in vitro, whereas Mdivi-1, a mitophagy inhibitor, prevented these effects on PK-15 cells as well as, more crucially, necroptosis. In conclusion, the RIPK1/RIPK3/MLKL signal route of necroptosis, which may be controlled by mitophagy, mediated nephrotoxicity of FB1. Our findings clarify the underlying molecular pathways of FB1-induced nephrotoxicity.

Keywords:  Fumonisin B1; Mitophagy; Necroptosis; Nephrotoxicity; RIPK1/RIPK3/MLKL

DOI:  https://doi.org/10.1016/j.fct.2024.114714