bims-mikwok 2024-02-18 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒02‒18
24 papers selected by
Gavin McStay, Liverpool John Moores University

The HRI branch of the integrated stress response selectively triggers mitophagy.
Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
Did mitophagy follow the origin of mitochondria?
Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
Renal aging and mitochondrial quality control.
Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
A system for inducible mitochondria-specific protein degradation in vivo.
The role of mitophagy in metabolic diseases and its exercise intervention.
Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.
Ceramides and mitochondrial homeostasis.
FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.
Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.
Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.
Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells.
A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.
A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells.
The potent paracrine effect of umbilical cord mesenchymal stem cells mediates mitochondrial quality control to restore chemotherapy-induced damage in ovarian granulosa cells.
Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.
Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
Sacubitril/valsartan ameliorates tubulointerstitial fibrosis by restoring mitochondrial homeostasis in diabetic kidney disease.

Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]

The HRI branch of the integrated stress response selectively triggers mitophagy.

Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.

  To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.

Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control

DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
Nat Commun. 2024 Feb 10. 15(1): 1252

Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.

Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.

Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.

DOI: https://doi.org/10.1038/s41467-024-45651-y
Autophagy. 2024 Feb 15. 1-9

Did mitophagy follow the origin of mitochondria?

Mauro Degli Esposti.

  Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy signaling.Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; ATG, autophagy related; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CALCOCO, calcium binding and coiled-coil domain; CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FBXL4, F-box and leucine rich repeat protein 4; FUNDC1, FUN14 domain containing 1; GABARAPL1, GABA type A receptor associated protein like 1; HIF, hypoxia inducible factor; IMM, inner mitochondrial membrane; LBPA/BMP, lysobisphosphatidic acid; LIR, LC3-interacting region; LPA, lysophosphatidic acid; MAM, mitochondria-associated membranes; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MCL, monolysocardiolipin; ML, maximum likelihood; NBR1, NBR1 autophagy cargo receptor; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PACS2, phosphofurin acidic cluster sorting protein 2; PC/PLC, phosphatidylcholine; PE, phosphatidylethanolamine; PHB2, prohibitin 2; PINK1, PTEN induced kinase 1; PtdIns, phosphatidylinositol; SAR, Stramenopiles, Apicomplexa and Rhizaria; TAX1BP1, Tax1 binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; VDAC/porin, voltage dependent anion channel.

Keywords:  BNIP3; cardiolipin; evolution; membrane dynamics; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2307215
Nat Commun. 2024 Feb 13. 15(1): 1328

Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

DOI: https://doi.org/10.1038/s41467-024-45524-4
Aging Cell. 2024 Feb 15. e14103

Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.

Tse Yu Chen, Feng-Yung Wang, Pin-Jung Lee, Ao-Lin Hsu, Tsui-Ting Ching.

  S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt ) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt , suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.

Keywords:  S-adenosyl methionine; UPRmt; longevity; mitochondrial tRNA methyltransferase

DOI:  https://doi.org/10.1111/acel.14103
Biogerontology. 2024 Feb 13.

Renal aging and mitochondrial quality control.

Xiuli Guo, Jiao Wang, Yinjie Wu, Xinwang Zhu, Li Xu.

  Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Keywords:  Aging; Mitochondrial dysfunction; Mitochondrial quality control; Renal intrinsic cells

DOI:  https://doi.org/10.1007/s10522-023-10091-6
bioRxiv. 2024 Feb 01. pii: 2024.01.30.577830. [Epub ahead of print]

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.

Nicole Madrazo, Zinia Khattar, Evan T Powers, Jessica D Rosarda, R Luke Wiseman.

Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the biological mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress, including the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the specific stress signaling pathways activated in response to mitochondrial proteostasis stress by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of individual mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to mitochondrial proteostasis stress, with no other pathway showing significant activation. Further expanding this study, we show that broad depletion of mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to mitochondrial proteostasis disruption.

DOI: https://doi.org/10.1101/2024.01.30.577830
Nat Commun. 2024 Feb 16. 15(1): 1454

A system for inducible mitochondria-specific protein degradation in vivo.

Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.

Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.

DOI: https://doi.org/10.1038/s41467-024-45819-6
Front Physiol. 2024 ;15 1339128

The role of mitophagy in metabolic diseases and its exercise intervention.

Shaokai Tang, Yuanwen Geng, Qinqin Lin.

  Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.

Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.3389/fphys.2024.1339128
Development. 2024 Feb 12. pii: dev.201732. [Epub ahead of print]

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.

Bhavin Uttekar, Rahul Kumar Verma, Darshika Tomer, Richa Rikhy.

  Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1 depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2, and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2, and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1 depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation, and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.

Keywords:   Drosophila ; APKC; Drp1; Epithelial polarity; Mitochondria; Opa1; ROS

DOI:  https://doi.org/10.1242/dev.201732
FEBS J. 2024 Feb 16.

Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.

Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.

  Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.

Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1111/febs.17083
Circulation. 2024 Feb 16.

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.

Bowen Li, Fangfang Liu, Xihui Chen, Tangdong Chen, Juan Zhang, Yifeng Liu, Yan Yao, Weihong Hu, Mengjie Zhang, Bo Wang, Liwen Liu, Kun Chen, Yuanming Wu.

  BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable myocardiopathy. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the myocardiopathy phenotype.METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification.
RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis.
CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

Keywords:  autophagy; cardiomyopathies; heart failure; ligases; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.064489
Cell Signal. 2024 Feb 13. pii: S0898-6568(24)00067-6. [Epub ahead of print] 111099

Ceramides and mitochondrial homeostasis.

Song Ding, Guorui Li, Tinglv Fu, Tianyu Zhang, Xiao Lu, Ning Li, Qing Geng.

  Lipotoxicity arises from the accumulation of lipid intermediates in non-adipose tissue, precipitating cellular dysfunction and death. Ceramide, a toxic byproduct of excessive free fatty acids, has been widely recognized as a primary contributor to lipotoxicity, mediating various cellular processes such as apoptosis, differentiation, senescence, migration, and adhesion. As the hub of lipid metabolism, the excessive accumulation of ceramides inevitably imposes stress on the mitochondria, leading to the disruption of mitochondrial homeostasis, which is typified by adequate ATP production, regulated oxidative stress, an optimal quantity of mitochondria, and controlled mitochondrial quality. Consequently, this review aims to collate current knowledge and facts regarding the involvement of ceramides in mitochondrial energy metabolism and quality control, thereby providing insights for future research.

Keywords:  Ceramide; ETC; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1016/j.cellsig.2024.111099
Redox Biol. 2024 Feb 09. pii: S2213-2317(24)00057-0. [Epub ahead of print]70 103081

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.

Miyesaier Abudureyimu, Xuanming Luo, Lingling Jiang, Xuejuan Jin, Cuizhen Pan, Wei Yu, Junbo Ge, Yingmei Zhang, Jun Ren.

  AIMS: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF.METHOD AND RESULTS: Adult mice were placed on a high fat diet plus l-NAME in drinking water ('two-hit' challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in 'two-hit' mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a 'double-damage' insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated 'double-damage'-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated 'two-hit' or 'double-damage'-induced changes in SERCA2a, phospholamban and mitochondrial injury.
CONCLUSION: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.

Keywords:  Drp1; FBXL4; HFpEF; Intracellular Ca(2+); Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.redox.2024.103081
Cardiovasc Toxicol. 2024 Feb 14.

Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.

Zhaohui Pei, Yayuan Xiong, Shasha Jiang, Rui Guo, Wei Jin, Jun Tao, Zhenzhong Zhang, Yingmei Zhang, Yunzeng Zou, Yan Gong, Jun Ren.

  Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4 °C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3 weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.

Keywords:  Autophagy; Cold stress; Metallothionein; Mitophagy; Myocardial function

DOI:  https://doi.org/10.1007/s12012-023-09823-4
Diabetes Metab J. 2024 Feb 15.

Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.

Songling Tang, Di Hao, Wen Ma, Lian Liu, Jiuyu Gao, Peng Yao, Haifang Yu, Lu Gan, Yu Cao.

  Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca2+ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

Keywords:  Diabetes mellitus; Heart diseases; Mitophagy; Obesity; PTEN-induced putative kinase; Parkin protein

DOI:  https://doi.org/10.4093/dmj.2023.0213
Aging (Albany NY). 2024 Feb 12. 16

Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells.

Mauro Cozzolino, Yagmur Ergun, Emma Ristori, Akanksha Garg, Gizem Imamoglu, Emre Seli.

  Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) by promoting the breakdown of misfolded proteins and setting in motion a cascade of reactions to re-establish protein homeostasis. Global germline deletion of Clpp in mice results in female infertility and accelerated follicular depletion. Telomeres are tandem repeats of 5'-TTAGGG-3' sequences found at the ends of the chromosomes. Telomeres are essential for maintaining chromosome stability during somatic cell division and their shortening is associated with cellular senescence and aging. In this study, we asked whether the infertility and ovarian aging phenotype caused by global germline deletion of Clpp is associated with somatic aging, and tested telomere length in tissues of young and aging mice. We found that impaired mtUPR caused by the lack of CLPP is associated with accelerated telomere shortening in both oocytes and somatic cells of aging mice. In addition, expression of several genes that maintain telomere integrity was decreased, and double-strand DNA breaks were increased in telomeric regions. Our results highlight how impaired mtUPR can affect telomere integrity and demonstrate a link between loss of mitochondrial protein hemostasis, infertility, and somatic aging.

Keywords:  Clpp; aging; mitochondrial dysfunction; telomere length; unfolded protein response

DOI:  https://doi.org/10.18632/aging.205543
Microb Pathog. 2024 Feb 08. pii: S0882-4010(24)00037-8. [Epub ahead of print]188 106570

A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.

Ran Kun Zuo, Can Wang, Zhi Yuan Yu, Hui Min Shi, Xiao Kun Song, Shen Dong Zhou, Na Na Ma, Guang Jun Chang, Xiang Zhen Shen.

  High-concentrate diet induce subacute ruminal acidosis (SARA) and cause liver damage in ruminants. It has been reported that forkhead box protein A2 (FOXA2) can enhance mitochondrial membrane potential but its function in mitochondrial dysfunction induced by high concentrate diets is still unknown. Therefore, the aim of this study was to elucidate the effect of high-concentrate (HC) diet on hepatic FOXA2 expression, mitochondrial unfolded protein response (UPRmt), mitochondrial dysfunction and oxidative stress. A total of 12 healthy mid-lactation Holstein cows were selected and randomized into 2 groups: the low concentrate (LC) diet group (concentrate:forage = 4:6) and HC diet group (concentrate:forage = 6:4). The trial lasted 21 d. The rumen fluid, blood and liver tissue were collected at the end of the experiment. The results showed that the rumen fluid pH level was reduced in the HC group and the pH was lower than 5.6 for more than 4 h/d, indicating that feeding HC diets successfully induced SARA in dairy cows. Both FOXA2 mRNA and protein abundance were significantly reduced in the liver of the HC group compared with the LC group. The activity of antioxidant enzymes (CAT, G6PDH, T-SOD, Cu/Zn SOD, Mn SOD) and mtDNA copy number in the liver tissue of the HC group decreased, while the level of H2O2 significantly increased, this increase was accompanied by a decrease in oxidative phosphorylation (OXPHOS). The balance of mitochondrial division and fusion was disrupted in the HC group, as evidenced by the decreased mRNA level of OPA1, MFN1, and MFN2 and increased mRNA level of Drp1, Fis1, and MFF. At the same time, HC diet downregulated the expression level of SIRT1, SIRT3, PGC-1α, TFAM, and Nrf 1 to inhibit mitochondrial biogenesis. The HC group induced UPRmt in liver tissue by upregulating the mRNA and protein levels of CLPP, LONP1, CHOP, Hsp10, and Hsp60. In addition, HC diet could increase the protein abundance of Bax, CytoC, Caspase 3 and Cleaved-Caspase 3, while decrease the protein abundance of Bcl-2 and the Bcl-2/Bax ratio. Overall, our study suggests that the decreased expression of FOXA2 may be related to UPRmt, mitochondrial dysfunction, oxidative stress, and apoptosis in the liver of dairy cows fed a high concentrate diet.

Keywords:  FOXA2; High-concentrate diet; Liver; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/j.micpath.2024.106570
Nat Neurosci. 2024 Feb 15.

A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.

Paula R Haynes, Elana S Pyfrom, Yongjun Li, Carly Stein, Vishnu Anand Cuddapah, Jack A Jacobs, Zhifeng Yue, Amita Sehgal.

Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.

DOI: https://doi.org/10.1038/s41593-023-01568-1
Chem Biol Interact. 2024 Feb 13. pii: S0009-2797(24)00050-4. [Epub ahead of print] 110904

Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells.

Wenhui Shen, Xianhui Zeng, Xiangchen Zeng, Baoshan Hu, Chong Ren, Zhiming Lin, Long Zhang, Gang Rui, Miersalijiang Yasen, Xiaohui Chen.

  Osteosarcoma is a prevalent kind of primary bone malignancy. Trifluoperazine, as an antipsychotic drug, has anti-tumor activity against a variety of cancers. Nevertheless, the impact of trifluoperazine on osteosarcoma is unclear. Our investigation aimed to explore the mechanism of trifluoperazine's effect on osteosarcoma. We found that trifluoperazine inhibited 143B and U2-OS osteosarcoma cell proliferation in a method based on the dose. Furthermore, it was shown that trifluoperazine induced the accumulation of reactive oxygen species (ROS) to cause mitochondrial damage and induced mitophagy in osteosarcoma cells. Finally, combined with RNA-seq results, we first demonstrated the AMPK/mTOR/ULK1 signaling pathway as a potential mechanism of trifluoperazine-mediated mitophagy in osteosarcoma cells and can be suppressed by AMPK inhibitor Compound C.

Keywords:  AMPK; Mitophagy; Osteosarcoma; Trifluoperazine; ULK1; mTOR

DOI:  https://doi.org/10.1016/j.cbi.2024.110904
Biomed Pharmacother. 2024 Feb 12. pii: S0753-3322(24)00144-6. [Epub ahead of print]172 116263

The potent paracrine effect of umbilical cord mesenchymal stem cells mediates mitochondrial quality control to restore chemotherapy-induced damage in ovarian granulosa cells.

Jin Seok, Hang-Soo Park, Esra Cetin, Mohammad Mousaei Ghasroldasht, Farzana Begum Liakath, Ayman Al-Hendy.

  The basic principle of chemotherapy is to attack cells with fast growth, and cancer cells are targeted by anticancer drugs because they have a faster growth rate than normal cells. High doses of anticancer drugs may cause an irreversible decline in reproductive capacity, and novel approaches for fertility preservation and/or restoration after anticancer treatment are urgently needed. Here, we provide important insights into the recovery of human reproductive cells damaged by chemotherapy. We performed a detailed screening of the cytokines of various human mesenchymal stem cells (hMSCs) to select superior MSCs. Also, we analyzed the Ovarian granulosa cell (OGC)-)-specific functions for restoring function, apoptosis, and mitochondrial functions to confirm the recovery mechanism in damaged OGCs. As a result, we demonstrated that conditioned media (CM) of Umbilical cord mesenchymal stem cells (UC-MSCs) could restore the functions of damaged OGCs primarily through antiapoptotic and antioxidant effects. Furthermore, CM changed the phenotype of damaged OGCs to an energetic status by restoring mitochondrial function and enhanced the mitochondrial metabolic activity decreased by chemotherapy. Finally, we demonstrated that the restoration of mitochondrial function in damaged OGCs was mediated through mitochondrial autophagy (mitophagy). Our findings offer new insights into the potential of stem cell-based therapy for fertility preservation and/or restoration in female cancer patients.

Keywords:  Chemotherapy; Infertility; Mesenchymal Stem Cells; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.biopha.2024.116263
Curr Neuropharmacol. 2024 Jan 31.

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

Kewarin Jinawong, Chanon Piamsiri, Nattayaporn Apaijai, Chayodom Maneechote, Busarin Arunsak, Wichwara Nawara, Chanisa Thonusin, Hiranya Pintana, Nipon Chattipakorn, Siriporn C Chattipakorn.

  BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). <P> Objective: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril.METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. <P> Results: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. <P> Conclusion: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Keywords:  Myocardial infarction; brain metabolism; cognitive impairment; mitochondrial dysfunction.; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.2174/1570159X22666240131114913
ACS Appl Mater Interfaces. 2024 Feb 12.

Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.

Liku Biswal, Mohammed Nadim Sardoiwala, Avinash Chandra Kushwaha, Syamantak Mukherjee, Surajit Karmakar.

  The molecular pathways that melatonin follows as a Parkinson's disease (PD) antagonist remain poorly elucidated, despite it being a safe and a potential neurotherapeutic drug with a few limitations such as less bioavailability, premature oxidation, brain delivery, etc. Here, we used a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain. This nanomelatonin showed better antioxidative and neuroprotective properties, and it not only improves mitophagy to remove unhealthy mitochondria but also improves mitochondrial biogenesis to counteract rotenone-induced toxicity in an in vitro PD model. We also showed BMI1, a member of the PRC1 complex that regulates mitophagy, whose protein expression was enhanced after nanomelatonin dosage. These effects were translated to a rodent model, where nanomelatonin improves the TH+ve neuron population in SNPC and protects against rotenone-mediated toxicity. Our findings highlight the significantly better in vitro and in vivo neuroprotective effect of nanomelatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy as a measure of the potential therapeutic candidate for PD.

Keywords:  BMI1; PTEN; Parkinson’s disease; melatonin; mitophagy

DOI:  https://doi.org/10.1021/acsami.3c17092
Diabetol Metab Syndr. 2024 Feb 10. 16(1): 40

Sacubitril/valsartan ameliorates tubulointerstitial fibrosis by restoring mitochondrial homeostasis in diabetic kidney disease.

Xing-Jian Zhang, Cong-Cong Liu, Zuo-Lin Li, Lin Ding, Yan Zhou, Dong-Jie Zhang, Yao Zhang, Shu-Ting Hou, Rui-Xia Ma.

  BACKGROUND: Tubulointerstitial fibrosis plays an important role in the progression of diabetic kidney disease (DKD). Sacubitril/valsartan (Sac/Val) exerts a robust beneficial effect in DKD. However, the potential functional effect of Sac/Val on tubulointerstitial fibrosis in DKD is still largely unclear.METHODS: Streptozotocin-induced diabetic mice were given Sac/Val or Val by intragastric administration once a day for 12 weeks. The renal function, the pathological changes of tubule injury and tubulointerstitial fibrosis, as well as mitochondrial morphology of renal tubules in mice, were evaluated. Genome-wide gene expression analysis was performed to identify the potential mechanisms. Meanwhile, human tubular epithelial cells (HK-2) were cultured in high glucose condition containing LBQ657/valsartan (LBQ/Val). Further, mitochondrial functions and Sirt1/PGC1α pathway of tubular epithelial cells were assessed by Western blot, Real-time-PCR, JC-1, MitoSOX or MitoTracker. Finally, the Sirt1 specific inhibitor, EX527, was used to explore the potential effects of Sirt1 signaling in vivo and in vitro.
RESULTS: We found that Sac/Val significantly ameliorated the decline of renal function and tubulointerstitial fibrosis in DKD mice. The enrichment analysis of gene expression indicated metabolism as an important modulator in DKD mice with Sac/Val administration, in which mitochondrial homeostasis plays a pivotal role. Then, the decreased expression of Tfam and Cox IV;, as well as changes of mitochondrial function and morphology, demonstrated the disruption of mitochondrial homeostasis under DKD conditions. Interestingly, Sac/Val administration was found to restore mitochondrial homeostasis in DKD mice and in vitro model of HK-2 cells. Further, we demonstrated that Sirt1/PGC1α, a crucial pathway in mitochondrial homeostasis, was activated by Sac/Val both in vivo and in vitro. Finally, the beneficial effects of Sac/Val on mitochondrial homeostasis and tubulointerstitial fibrosis was partially abolished in the presence of Sirt1 specific inhibitor.
CONCLUSIONS: Taken together, we demonstrate that Sac/Val ameliorates tubulointerstitial fibrosis by restoring Sirt1/PGC1α pathway-mediated mitochondrial homeostasis in DKD, providing a theoretical basis for delaying the progression of DKD in clinical practice.

Keywords:  Diabetic kidney disease; Mitochondria; PGC1α; Sacubitril/valsartan; Sirt1; Tubulointerstitial fibrosis

DOI:  https://doi.org/10.1186/s13098-024-01284-1