bims-mikwok 2024-07-21 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒07‒21
twenty-two papers selected by
Gavin McStay, Liverpool John Moores University

MEC-12/alpha tubulin regulates mitochondrial distribution and mitophagy during oxidative stress in C. elegans.
Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
Mitophagy-related regulated cell death: molecular mechanisms and disease implications.
ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.
HIF-1α limits myocardial infarction by promoting mitophagy in mouse hearts adapted to chronic hypoxia.
Mitochondrial Fission Is Involved in Heat Resistance in Zebrafish.
A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle.
MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer's Disease.
Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.
GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.
CISD2 regulates oxidative stress and mitophagy to maintain the balance of the follicular microenvironment in PCOS.
Quantitative 3D electron microscopy characterization of mitochondrial structure, mitophagy, and organelle interactions in murine atrial fibrillation.
Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.
Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles.
Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation.
Isotoosendanin inhibits triple-negative breast cancer metastasis by reducing mitochondrial fission and lamellipodia formation regulated by the Smad2/3-GOT2-MYH9 signaling axis.
Yttrium oxide nanoparticles alleviate cognitive deficits, neuroinflammation, and mitochondrial biogenesis impairment induced by streptozotocin.
Phytochemicals targeting mitophagy: Therapeutic opportunities and prospects for treating Alzheimer's disease.
Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.
Detection of a Mitochondrial Fragmentation and Integrated Stress Response Using the Cell Painting Assay.
An adaptor for feedback regulation of heme biosynthesis by the mitochondrial protease CLPXP.
HTR1B regulates mitochondrial homeostasis and mitophagy by activating the ERK/ MAPK signalling pathway during human embryonic arrest.

MicroPubl Biol. 2024 ;2024

MEC-12/alpha tubulin regulates mitochondrial distribution and mitophagy during oxidative stress in C. elegans.

Fivos Borbolis, Myrsini Kteniadaki, Konstantinos Palikaras.

Mitophagy, the selective removal of dysfunctional mitochondria, is pivotal for the maintenance of neuronal function and survival. MEC-12/α-tubulin contributes to neuronal physiology through the regulation of microtubule assembly, intracellular transport and mitochondrial distribution. However, its role in mitochondrial dynamics and mitophagy remains obscure. Here, we demonstrate that MEC-12 influences mitochondrial morphology under basal conditions and regulates the axonal mitochondrial population. Impairment of MEC-12 results in compromised axonal mitophagy under both basal conditions and oxidative stress. Our results uncover the critical role of MEC-12/α-tubulin for maintaining a healthy mitochondrial population in axons and highlight the complex interplay between microtubules, mitophagy and neuronal health.

DOI: https://doi.org/10.17912/micropub.biology.001232
Geroscience. 2024 Jul 19.

Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.

Annika Traa, Aura A Tamez González, Jeremy M Van Raamsdonk.

  The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell's ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

Keywords:   C. elegans ; Aging; Biological resilience; DRP1; Insulin/IGF-1 signaling; Mitochondrial fission

DOI:  https://doi.org/10.1007/s11357-024-01276-z
Cell Death Dis. 2024 Jul 16. 15(7): 505

Mitophagy-related regulated cell death: molecular mechanisms and disease implications.

Molin Yang, Xiang Wei, Xin Yi, Ding-Sheng Jiang.

During oxidative phosphorylation, mitochondria continuously produce reactive oxygen species (ROS), and untimely ROS clearance can subject mitochondria to oxidative stress, ultimately resulting in mitochondrial damage. Mitophagy is essential for maintaining cellular mitochondrial quality control and homeostasis, with activation involving both ubiquitin-dependent and ubiquitin-independent pathways. Over the past decade, numerous studies have indicated that different forms of regulated cell death (RCD) are connected with mitophagy. These diverse forms of RCD have been shown to be regulated by mitophagy and are implicated in the pathogenesis of a variety of diseases, such as tumors, degenerative diseases, and ischemia‒reperfusion injury (IRI). Importantly, targeting mitophagy to regulate RCD has shown excellent therapeutic potential in preclinical trials, and is expected to be an effective strategy for the treatment of related diseases. Here, we present a summary of the role of mitophagy in different forms of RCD, with a focus on potential molecular mechanisms by which mitophagy regulates RCD. We also discuss the implications of mitophagy-related RCD in the context of various diseases.

DOI: https://doi.org/10.1038/s41419-024-06804-5
Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00802-7. [Epub ahead of print]43(8): 114473

ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.

John Kim, Madeleine Goldstein, Lauren Zecchel, Ryan Ghorayeb, Christopher A Maxwell, Hilla Weidberg.

  Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health.

Keywords:  AAA ATPase; ATAD1; CP: Cell biology; CP: Metabolism; TOM clogging; mitochondrial protein import; mitochondrial stress; protein quality control; proteotoxicity

DOI:  https://doi.org/10.1016/j.celrep.2024.114473
Acta Physiol (Oxf). 2024 Jul 17. e14202

HIF-1α limits myocardial infarction by promoting mitophagy in mouse hearts adapted to chronic hypoxia.

Petra Alanova, Lukas Alan, Barbora Opletalova, Romana Bohuslavova, Pavel Abaffy, Katerina Matejkova, Kristyna Holzerova, Daniel Benak, Nina Kaludercic, Roberta Menabo, Fabio Di Lisa, Bohuslav Ostadal, Frantisek Kolar, Gabriela Pavlinkova.

  AIM: The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood.METHODS: Male wild-type (WT) mice and mice with partial Hif1a deficiency (hif1a+/-) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy.
RESULTS: We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a+/- mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection.
CONCLUSION: These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.

Keywords:  cardioprotection; chronic hypoxia; hypoxia‐inducible factor 1 alpha; mitochondria; mitophagy; myocardial infarction

DOI:  https://doi.org/10.1111/apha.14202
Zebrafish. 2024 Jul 15.

Mitochondrial Fission Is Involved in Heat Resistance in Zebrafish.

Yousheng Mao, KwangHeum Hong, Li Li, In-Koo Nam, Seok-Hyung Kim, Seong-Kyu Choe.

  Global warming and extreme weather events pose a significant threat to global biodiversity, with rising water temperatures exerting a profound influence on fish conservation and fishery development. In this study, we used zebrafish as a model organism to explore the impact of a heat acclimation period on their survival rates. The results demonstrated that a 2-month heat acclimation period almost completely mitigated heat stress-induced mortality in zebrafish. Subsequent analysis of the surviving zebrafish revealed a predominance of hepatic mitochondria in a fission state. Remarkably, a short-term fasting regimen, which induced hepatic mitochondrial fission, mirrored the outcomes of the protective effect of heat acclimation and augmented animal survival under heat stress. Conversely, treatment with a mitochondrial fission inhibitor within the fasting group attenuated the elevated survival rate. Furthermore, zebrafish embryos subjected to brief heat acclimation also exhibited increased heat resistance, a trait diminished by a chemical intervention inhibiting mitochondrial fission. This suggests a shared mechanism for heat resistance between embryos and adult zebrafish. These findings underscore the potential use of inducing mitochondrial fission to enhance heat resistance in zebrafish, offering promise for fish biodiversity conservation in the face of global warming.

Keywords:  heat acclimation; heat resistance; heat stress; mitochondrial fission; zebrafish

DOI:  https://doi.org/10.1089/zeb.2024.0128
Acta Physiol (Oxf). 2024 Jul 18. e14203

A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle.

Francisco Díaz-Castro, Mauro Tuñón-Suárez, Patricia Rivera, Javier Botella, Jorge Cancino, Ana María Figueroa, Juan Gutiérrez, Claudette Cantin, Louise Deldicque, Hermann Zbinden-Foncea, Joachim Nielsen, Carlos Henríquez-Olguín, Eugenia Morselli, Mauricio Castro-Sepúlveda.

  AIM: The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM).METHODS: Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy.
RESULTS: Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1Ser616) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM.
CONCLUSION: The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.

Keywords:  BNIP3L/NIX; mitochondria cristae; mitochondria dynamics; mitophagy

DOI:  https://doi.org/10.1111/apha.14203
Neurochem Res. 2024 Jul 13.

MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer's Disease.

Jian-Sheng Luo, Wen-Hu Zhai, Ling-Ling Ding, Xian-Jie Zhang, Jia Han, Jia-Qi Ning, Xue-Meng Chen, Wen-Cai Jiang, Ru-Yu Yan, Meng-Jie Chen.

  Alzheimer's disease (AD) represents the most widespread neurodegenerative disorder, distinguished by a gradual onset and slow progression, presenting a substantial challenge to global public health. The mitochondrial-associated membrane (MAMs) functions as a crucial center for signal transduction and material transport between mitochondria and the endoplasmic reticulum, playing a pivotal role in various pathological mechanisms of AD. The dysregulation of mitochondrial quality control systems is considered a fundamental factor in the development of AD, leading to mitochondrial dysfunction and subsequent neurodegenerative events. Recent studies have emphasized the role of MAMs in regulating mitochondrial quality control. This review will delve into the molecular mechanisms underlying the imbalance in mitochondrial quality control in AD and provide a comprehensive overview of the role of MAMs in regulating mitochondrial quality control.

Keywords:  Alzheimer’s disease; MAMs; Mitochondrial quality control

DOI:  https://doi.org/10.1007/s11064-024-04205-w
Cell Death Differ. 2024 Jul 15.

Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.

Saiyan Bian, Wenkai Ni, Linlin Zhou, Yun Tong, Chengchen Dai, Xuying Zhao, Yuwei Qiang, Jie Gao, Yifu Xiao, Wei Liu, Changsheng Chen, Shengli Lin, Jianing Gong, Suming Zhao, Yinqi Chen, Zhaoyi Lin, Dong Liu, Hui Zhao, Wenjie Zheng.

Although deubiquitinases (DUBs) have been well described in liver tumorigenesis, their potential roles and mechanisms have not been fully understood. In this study, we identified ubiquitin-specific protease 1 (USP1) as an oncogene with essential roles during hepatocellular carcinoma (HCC) progression. USP1, with elevated expression levels and clinical significance, was identified as a hub DUB for HCC in multiple bioinformatics datasets. Functionally, USP1 overexpression significantly enhanced the malignant behaviors in HCC cell lines and spheroids in vitro, as well as the zebrafish model and the xenograft model in vivo. In contrast, genetic ablation or pharmacological inhibition of USP1 dramatically impaired the phenotypes of HCC cells. Specifically, ectopic USP1 enhanced aggressive properties and metabolic reprogramming of HCC cells by modulating mitochondrial dynamics. Mechanistically, USP1 induced mitochondrial fission by enhancing phosphorylation of Drp1 at Ser616 via deubiquitination and stabilization of cyclin-dependent kinase 5 (CDK5), which could be degraded by the E3 ligase NEDD4L. The USP1/CDK5 modulatory axis was activated in HCC tissues, which was correlated with poor prognosis of HCC patients. Furthermore, Prasugrel was identified as a candidate USP1 inhibitor for targeting the phenotypes of HCC by an extensive computational study combined with experimental validations. Taken together, USP1 induced malignant phenotypes and metabolic reprogramming by modulating mitochondrial dynamics in a CDK5-mediated Drp1 phosphorylation manner, thereby deteriorating HCC progression.

DOI: https://doi.org/10.1038/s41418-024-01342-1
Cell Death Differ. 2024 Jul 16.

GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.

Jia-Hui Zhu, Shen-Xi Ouyang, Guo-Yan Zhang, Qi Cao, Rujuan Xin, Hang Yin, Jing-Wen Wu, Yan Zhang, Zhen Zhang, Yi Liu, Jiang-Tao Fu, Yi-Ting Chen, Jie Tong, Jia-Bao Zhang, Jian Liu, Fu-Ming Shen, Dong-Jie Li, Pei Wang.

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1β (IL-1β)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

DOI: https://doi.org/10.1038/s41418-024-01343-0
Redox Rep. 2024 Dec;29(1): 2377870

CISD2 regulates oxidative stress and mitophagy to maintain the balance of the follicular microenvironment in PCOS.

Hong-Hui Wu, Qi Zhu, Na Liang, Yu Xiang, Tian-Yue Xu, Zi-Chao Huang, Jie-Yu Cai, Ling-Lin Weng, Hong-Shan Ge.

  OBJECTIVES: To observe the CISD2 expression among PCOS patients and to explore its profound impact on the follicular microenvironment. Moreover, we want to elucidate the intricate mechanistic contribution of CISD2 to the onset and progression of PCOS.METHODS: Oxidase NOX2, mitophagy-related proteins, and CISD2 were detected by WB. The changes in mitochondrial structure and quantity were observed by transmission electron microscopy. Mitochondrial and lysosome colocalization was used to detect the changes of mitophagy. MDA kit, GSH and GSSG Assay kit and ROS probe were used to detect oxidative stress damage.
RESULTS: We found that CISD2, mitophagy and oxidase in the GCs of PCOS patients were significantly increased. Testosterone stimulation leads to the increase of oxidase, mitophagy, and CISD2 in KGN cells. CISD2 inhibition promoted the increase of mitophagy, and the activation of mitochondria-lysosome binding, while alleviating the oxidative stress.
CONCLUSIONS: Inhibition of CISD2 can improve the occurrence of oxidative stress by increasing the level of mitophagy, thus affecting the occurrence and development of PCOS diseases.

Keywords:  CDGSH iron sulfur domain 2; hyperandrogenemia; mitophagy; oxidative stress; polycystic ovary syndrome

DOI:  https://doi.org/10.1080/13510002.2024.2377870
J Struct Biol. 2024 Jul 14. pii: S1047-8477(24)00050-9. [Epub ahead of print]216(3): 108110

Quantitative 3D electron microscopy characterization of mitochondrial structure, mitophagy, and organelle interactions in murine atrial fibrillation.

Pavithran Guttipatti, Najla Saadallah, Ruiping Ji, Uma Mahesh R Avula, Christopher N Goulbourne, Elaine Y Wan.

  Atrial fibrillation (AF) is the most common clinical arrhythmia, however there is limited understanding of its pathophysiology including the cellular and ultrastructural changes rendered by the irregular rhythm, which limits pharmacological therapy development. Prior work has demonstrated the importance of reactive oxygen species (ROS) and mitochondrial dysfunction in the development of AF. Mitochondrial structure, interactions with other organelles such as sarcoplasmic reticulum (SR) and T-tubules (TT), and degradation of dysfunctional mitochondria via mitophagy are important processes to understand ultrastructural changes due to AF. However, most analysis of mitochondrial structure and interactome in AF has been limited to two-dimensional (2D) modalities such as transmission electron microscopy (EM), which does not fully visualize the morphological evolution of the mitochondria during mitophagy. Herein, we utilize focused ion beam-scanning electron microscopy (FIB-SEM) and perform reconstruction of three-dimensional (3D) EM from murine left atrial samples and measure the interactions of mitochondria with SR and TT. We developed a novel 3D quantitative analysis of FIB-SEM in a murine model of AF to quantify mitophagy stage, mitophagosome size in cardiomyocytes, and mitochondrial structural remodeling when compared with control mice. We show that in our murine model of spontaneous and continuous AF due to persistent late sodium current, left atrial cardiomyocytes have heterogenous mitochondria, with a significant number which are enlarged with increased elongation and structural complexity. Mitophagosomes in AF cardiomyocytes are located at Z-lines where they neighbor large, elongated mitochondria. Mitochondria in AF cardiomyocytes show increased organelle interaction, with 5X greater contact area with SR and are 4X as likely to interact with TT when compared to control. We show that mitophagy in AF cardiomyocytes involves 2.5X larger mitophagosomes that carry increased organelle contents. In conclusion, when oxidative stress overcomes compensatory mechanisms, mitophagy in AF faces a challenge of degrading bulky complex mitochondria, which may result in increased SR and TT contacts, perhaps allowing for mitochondrial Ca2+ maintenance and antioxidant production.

Keywords:  3D structure; Atrial fibrillation; Electron microscopy; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.jsb.2024.108110
bioRxiv. 2024 Jul 09. pii: 2024.07.05.602170. [Epub ahead of print]

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.

Michael O Isei, Meredith Crockett, Emily Chen, Joel Rodwell-Bullock, Trae Caroll, Peter A Girardi, Keith Nehrke, Gail Vw Johnson.

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans . Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.

DOI: https://doi.org/10.1101/2024.07.05.602170
Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2313609121

Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles.

Daniel A Peñalva, Ajay K Monnappa, Paolo Natale, Iván López-Montero.

  Mitofusins (Mfn1 and Mfn2) are the mitochondrial outer-membrane fusion proteins in mammals and belong to the dynamin superfamily of multidomain GTPases. Recent structural studies of truncated variants lacking alpha helical transmembrane domains suggested that Mfns dimerize to promote the approximation and the fusion of the mitochondrial outer membranes upon the hydrolysis of guanine 5'-triphosphate disodium salt (GTP). However, next to the presence of GTP, the fusion activity seems to require multiple regulatory factors that control the dynamics and kinetics of mitochondrial fusion through the formation of Mfn1-Mfn2 heterodimers. Here, we purified and reconstituted the full-length murine Mfn2 protein into giant unilamellar vesicles (GUVs) with different lipid compositions. The incubation with GTP resulted in the fusion of Mfn2-GUVs. High-speed video-microscopy showed that the Mfn2-dependent membrane fusion pathway progressed through a zipper mechanism where the formation and growth of an adhesion patch eventually led to the formation of a membrane opening at the rim of the septum. The presence of physiological concentration (up to 30 mol%) of dioleoyl-phosphatidylethanolamine (DOPE) was shown to be a requisite to observe GTP-induced Mfn2-dependent fusion. Our observations show that Mfn2 alone can promote the fusion of micron-sized DOPE-enriched vesicles without the requirement of regulatory cofactors, such as membrane curvature, or the assistance of other proteins.

Keywords:  giant unilamellar vesicles; membrane fusion; mitochondrial dynamics; mitofusin 2

DOI:  https://doi.org/10.1073/pnas.2313609121
iScience. 2024 Jul 19. 27(7): 110185

Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation.

Taru Hilander, Ryan Awadhpersad, Geoffray Monteuuis, Krystyna L Broda, Max Pohjanpelto, Elizabeth Pyman, Sachin Kumar Singh, Tuula A Nyman, Isabelle Crevel, Robert W Taylor, Ann Saada, Diego Balboa, Brendan J Battersby, Christopher B Jackson, Christopher J Carroll.

  Mitochondrial ribosomes (mitoribosomes) have undergone substantial evolutionary structural remodeling accompanied by loss of ribosomal RNA, while acquiring unique protein subunits located on the periphery. We generated CRISPR-mediated knockouts of all 14 unique (mitochondria-specific/supernumerary) human mitoribosomal proteins (snMRPs) in the small subunit to study the effect on mitoribosome assembly and protein synthesis, each leading to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Surprisingly, the stability of mS37 was reduced in all our snMRP knockouts of the small and large ribosomal subunits and patient-derived lines with mitoribosome assembly defects. A redox-regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.

Keywords:  biochemistry; biological sciences; cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110185
Acta Pharmacol Sin. 2024 Jul 15.

Isotoosendanin inhibits triple-negative breast cancer metastasis by reducing mitochondrial fission and lamellipodia formation regulated by the Smad2/3-GOT2-MYH9 signaling axis.

Jing-Nan Zhang, Ze Zhang, Zhen-Lin Huang, Qian Guo, Ze-Qi Wu, Chuang Ke, Bin Lu, Zheng-Tao Wang, Li-Li Ji.

  Triple-negative breast cancer (TNBC) is incurable and prone to widespread metastasis. Therefore, identification of key targets for TNBC progression is urgently needed. Our previous study revealed that isotoosendanin (ITSN) reduced TNBC metastasis by targeting TGFβR1. ITSN is currently used as an effective chemical probe to further discover the key molecules involved in TNBC metastasis downstream of TGFβR1. The results showed that GOT2 was the gene downstream of Smad2/3 and that ITSN decreased GOT2 expression by abrogating the activation of the TGF-β-Smad2/3 signaling pathway through directly binding to TGFβR1. GOT2 was highly expressed in TNBC, and its knockdown decreased TNBC metastasis. However, GOT2 overexpression reversed the inhibitory effect of ITSN on TNBC metastasis both in vitro and in vivo. GOT2 interacted with MYH9 and hindered its binding to the E3 ubiquitin ligase STUB1, thereby reducing MYH9 ubiquitination and degradation. Moreover, GOT2 also enhanced the translocation of MYH9 to mitochondria and thus induced DRP1 phosphorylation, thereby promoting mitochondrial fission and lamellipodia formation in TNBC cells. ITSN-mediated inhibition of mitochondrial fission and lamellipodia formation was associated with reduced GOT2 expression. In conclusion, ITSN prevented MYH9-regulated mitochondrial fission and lamellipodia formation in TNBC cells by enhancing MYH9 protein degradation through a reduction in GOT2 expression, thus contributing to its inhibition of TNBC metastasis.

Keywords:  DRP1; GOT2; MYH9; TNBC; isotoosendanin; mitochondrial fission

DOI:  https://doi.org/10.1038/s41401-024-01335-3
Neurosci Lett. 2024 Jul 16. pii: S0304-3940(24)00273-8. [Epub ahead of print] 137895

Yttrium oxide nanoparticles alleviate cognitive deficits, neuroinflammation, and mitochondrial biogenesis impairment induced by streptozotocin.

Pooya Baghaee, Mohammad Yoonesi, Delaram Eslimi Esfahani, Elmira Beirami, Leila Dargahi, Fatemeh Sadat Rashidi, Neda Valian.

  Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Yttrium oxide nanoparticles (Y2O3NPs) have recently attracted much attention for their potential anti-inflammatory and antioxidant properties. However, the effects of Y2O3NPs in animal models of AD are less studied. This study aimed to investigate the potential therapeutic effects of Y2O3NPs in streptozotocin (STZ)-treated rats, a reliable animal model of AD, with special emphasis on cognitive function, neuroinflammation, and mitochondrial biogenesis in the hippocampus. Male Wistar rats were stereotaxically injected with STZ (3 mg/kg, 3 µl/ventricle). Three weeks after STZ injection, cognitive function was assessed using the Morris water maze, elevated plus maze, and passive avoidance tasks. Intraperitoneal treatment with Y2O3NPs (0.1, 0.3, or 0.5 mg/kg) was started 24 h after the STZ injection and continued for 21 days. The mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and components involved in mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM) were measured in the hippocampus. The results indicated that STZ induced cognitive impairment and led to neuroinflammation and mitochondrial biogenesis impairment in the hippocampus of rats. Interestingly, treatment with Y2O3NPs effectively reduced STZ-induced cognitive deficits in a dose-dependent manner, possibly by attenuating neuroinflammation and mitochondrial biogenesis impairment. These findings suggest that Y2O3NPs can be considered as a promising therapeutic agent for treating or ameliorating the neuropathological effects associated with AD.

Keywords:  Alzheimer’s disease; Cognition; Mitochondrial biogenesis; Neuroinflammation; Yttrium oxide nanoparticles

DOI:  https://doi.org/10.1016/j.neulet.2024.137895
Biomed Pharmacother. 2024 Jul 13. pii: S0753-3322(24)01028-X. [Epub ahead of print]177 117144

Phytochemicals targeting mitophagy: Therapeutic opportunities and prospects for treating Alzheimer's disease.

Jing Yang, He Zhao, Shengtao Qu.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and the leading cause of age-related cognitive decline. Recent studies have established a close relationship between mitophagy and the pathogenesis of AD. Various phytochemicals have shown promising therapeutic effects in mitigating the onset and progression of AD. This review offers a comprehensive overview of the typical features of mitophagy and the underlying mechanisms leading to its occurrence in AD, highlighting its significance in the disease's pathogenesis and progression. Additionally, we examine the therapeutic mechanisms of synthetic drugs that induce mitophagy in AD. Finally, we summarize recent advances in research on phytochemicals that regulate mitophagy in the treatment of AD, potentially guiding the development of new anti-AD drugs.

Keywords:  Alzheimer’s disease; Autophagy; Mitophagy; Phytochemicals; Therapy

DOI:  https://doi.org/10.1016/j.biopha.2024.117144
bioRxiv. 2024 Jul 12. pii: 2024.07.09.602707. [Epub ahead of print]

Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.

Nidhi Raghuram, Adam Hughes.

Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism.

DOI: https://doi.org/10.1101/2024.07.09.602707
J Med Chem. 2024 Jul 17.

Detection of a Mitochondrial Fragmentation and Integrated Stress Response Using the Cell Painting Assay.

Soheila Rezaei Adariani, Daya Agne, Sandra Koska, Annina Burhop, Carina Seitz, Jens Warmers, Petra Janning, Malte Metz, Axel Pahl, Sonja Sievers, Herbert Waldmann, Slava Ziegler.

Mitochondria are cellular powerhouses and are crucial for cell function. However, they are vulnerable to internal and external perturbagens that may impair mitochondrial function and eventually lead to cell death. In particular, small molecules may impact mitochondrial function, and therefore, their influence on mitochondrial homeostasis is at best assessed early on in the characterization of biologically active small molecules and drug discovery. We demonstrate that unbiased morphological profiling by means of the cell painting assay (CPA) can detect mitochondrial stress coupled with the induction of an integrated stress response. This activity is common for compounds addressing different targets, is not shared by direct inhibitors of the electron transport chain, and enables prediction of mitochondrial stress induction for small molecules that are profiled using CPA.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01183
bioRxiv. 2024 Jul 06. pii: 2024.07.05.602318. [Epub ahead of print]

An adaptor for feedback regulation of heme biosynthesis by the mitochondrial protease CLPXP.

Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Julia R Kardon.

Heme biosynthesis is tightly coordinated such that essential heme functions including oxygen transport, respiration, and catalysis are fully supplied without overproducing toxic heme precursors and depleting cellular iron. The initial heme biosynthetic enzyme, ALA synthase (ALAS), exhibits heme-induced degradation that is dependent on the mitochondrial AAA+ protease complex CLPXP, but the mechanism for this negative feedback regulation had not been elucidated. By biochemical reconstitution, we have discovered that POLDIP2 serves as a heme-sensing adaptor protein to deliver ALAS for degradation. Similarly, loss of POLDIP2 strongly impairs ALAS turnover in cells. POLDIP2 directly recognizes heme-bound ALAS to drive assembly of the degradation complex. The C-terminal element of ALAS, truncation of which leads to a form of porphyria (XLDPP), is dispensable for interaction with POLDIP2 but necessary for degradation. Our findings establish the molecular basis for heme-induced degradation of ALAS by CLPXP, establish POLDIP2 as a substrate adaptor for CLPXP, and provide mechanistic insight into two forms of erythropoietic protoporphyria linked to CLPX and ALAS.

DOI: https://doi.org/10.1101/2024.07.05.602318
Heliyon. 2024 Jun 30. 10(12): e33132

HTR1B regulates mitochondrial homeostasis and mitophagy by activating the ERK/ MAPK signalling pathway during human embryonic arrest.

Si-Min Ding, Ling-Ge Shi, Zhen-Ping Cao, Na-Na Zhu, Yun-Yun Liu, Meng-Yao Wang, Shuang-Shuang Cui, Hui-Ru Cheng, Dan Liang, Yun-Xia Cao, Ya-Jing Liu.

  Background: Previous studies have shown that serotonin and its receptors are widely distributed in mammalian reproductive tisssues and play an important role in embryonic development. However, the specific effects of the serotonergic system on embryonic arrest (EA) and the underlying mechanism require further investigation.Methods: Chorionic villi were collected from patients with EA and healthy pregnant women. Western blotting (WB) and immunohistochemistry (IHC) were used to detect serotonin receptor 1B (HTR1B) levels and evaluate mitochondrial function. Additionally, HTR-8/SVneo cells were transfected with an HTR1B overexpression plasmid. Quantitative real-time polymerase chain reaction(qRT-PCR), Cell Counting Kit-8 (CCK-8), and wound healing assays were utilized to evaluate mitophagy level, cell proliferation and cell migration, respectively.
Results: We discovered elevated HTR1B levels in the chorionic villi of the patients with EA compared to controls. Concurrently, we observed enhanced levels of nucleus-encoded proteins including mitofilin, succinate dehydrogenase complex subunit A (SDHA), and cytochrome c oxidase subunit 4 (COXIV), along with the mitochondrial fusion protein optic atrophy 1(OPA1), fission proteins mitochondrial fission protein 1(FIS1) and mitochondrial fission factor (MFF) in the EA group. Additionally, there was an excessive mitophagy levels in EA group. Furthermore, a notable activation of mitogen-activated protein kinase (MAPK) signaling pathway proteins including extracellular regulating kinase (ERK), c-Jun N-terminal kinase (JNK), and P38 was observed in the EA group. By overexpressing HTR1B in HTR-8/SVneo cells, we observed a significant reduction in cell proliferation and migration. HTR1B overexpression also caused an increase in levels of SDHA and FIS1, as well as an upregulation of mitophagy. Notably, the ERK inhibitor U0126 effectively mitigated these effects.
Conclusion: These findings show that HTR1B influences mitochondrial homeostasis, promoting excessive mitophagy and impairing cell proliferation and migration by activating the MAPK signalling pathway during post-implantation EA. Therefore, HTR1B may serve as a potential therapeutic target for patients with EA.

Keywords:  Embryonic arrest; Excessive mitophagy; HTR1B; MAPK; Mitochondrial fission protein; Mitochondrial fusion protein

DOI:  https://doi.org/10.1016/j.heliyon.2024.e33132