bims-mikwok 2024-04-28 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒04‒28
24 papers selected by
Gavin McStay, Liverpool John Moores University

OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.
Geranylgeranylated-SCF FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.
Inhibiting Pink1/Parkin-mediated mitophagy enhances the anticancer effects of quercetin in hepatocellular carcinomaf.
The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
Inflammation and mitophagy are mitochondrial checkpoints to aging.
The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.
A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
Contribution of the Type III Secretion System (T3SS2) of Vibrio parahaemolyticus in Mitochondrial Stress in Human Intestinal Cells.
Regulation of mitochondrial fission by fatty acyl-coenzyme A.
Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.
Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
18β-Glycyrrhetinic acid protects against deoxynivalenol-induced liver injury via modulating ferritinophagy and mitochondrial quality control.
Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.
Aflatoxin B1-exposed hepatocyte-derived extracellular vesicles: Initiating hepatic stellate cell-mediated liver fibrosis through a p53-Parkin-dependent mitophagy pathway.
Erratum to "PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance".
HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons.
Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials.
Adenylate kinase 4 promotes neuronal energy metabolism and mitophagy in early cerebral ischemia via Parkin/PKM2 pathway.
Mitochondrial Fission in Nickel Nanoparticle-Induced Reproductive Toxicity: An In Vitro GC-1 Cell Study.
Low-dose BPA-induced neuronal energy metabolism dysfunction and apoptosis mediated by PINK1/parkin mitophagy pathway in juvenile rats.

Int J Mol Sci. 2024 Apr 22. pii: 4566. [Epub ahead of print]25(8):

OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.

Robert Gilkerson, Harpreet Kaur, Omar Carrillo, Isaiah Ramos.

  In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.

Keywords:  DRP1; OMA1; OPA1; apoptosis; autophagy; bioenergetics; cristae; fission; fusion; integrated stress response; mitochondria; transmembrane potential

DOI:  https://doi.org/10.3390/ijms25084566
Cancer Lett. 2024 Apr 24. pii: S0304-3835(24)00288-X. [Epub ahead of print] 216895

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Guangzhao Li, Zongqi Wang, Bixi Gao, Kun Dai, Xiaowang Niu, Xiang Li, Yunjiang Wang, Longyuan Li, Xin Wu, Haiying Li, Zhengquan Yu, Zhong Wang, Gang Chen.

  Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

Keywords:  Ankyrin repeat and zinc-finger domain-containing protein 1; CAT-tail; Glioblastoma; Mitochondrial Unfolded Protein Response; Protein aggresome; Ribosome related Quality Control

DOI:  https://doi.org/10.1016/j.canlet.2024.216895
bioRxiv. 2024 Apr 16. pii: 2024.04.16.589745. [Epub ahead of print]

Geranylgeranylated-SCF FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.

Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Anish Gudur, Hagar Ismail, Ritika Adhikari, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.

E3-ubiquitin ligases (E3s) are main components of the ubiquitin-proteasome system (UPS), as they determine substrate specificity in response to internal and external cues to regulate protein homeostasis. However, the regulation of membrane protein ubiquitination by E3s within distinct cell membrane compartments or organelles is not well understood. We show that FBXO10, the interchangeable component of the SKP1/CUL1/F-box ubiquitin ligase complex (SCF-E3), undergoes lipid-modification with geranylgeranyl isoprenoid at Cysteine953 (C953), facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide does not contain a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and the interaction with two cytosolic factors, PDE6δ (a prenyl group-binding protein), and HSP90 (a mitochondrial chaperone) orchestrate specific OMM targeting of prenyl-FBXO10 across diverse membrane compartments. The geranylgeranylation-deficient FBXO10(C953S) mutant redistributes away from the OMM, leading to impaired mitochondrial ATP production, decreased mitochondrial membrane potential, and increased mitochondrial fragmentation. Phosphoglycerate mutase 5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative mass spectrometry analyses of enriched mitochondria (LFQ-MS/MS), leveraging the redistribution of FBXO10(C953S). FBXO10, but not FBXO10(C953S), promoted polyubiquitylation and degradation of PGAM5. Examination of the role of this pathway in a physiological context revealed that the loss of FBXO10 or expression of prenylation-deficient-FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human iPSCs and murine myoblasts. Our studies identify a mechanism for selective E3-ligase mediated regulation of mitochondrial membrane proteostasis and metabolic health, potentially amenable to therapeutic intervention.

DOI: https://doi.org/10.1101/2024.04.16.589745
Biochem Biophys Res Commun. 2024 Apr 05. pii: S0006-291X(24)00435-2. [Epub ahead of print]712-713 149899

Inhibiting Pink1/Parkin-mediated mitophagy enhances the anticancer effects of quercetin in hepatocellular carcinomaf.

Fang Chen.

  Quercetin, a naturally occurring flavonoid, has been investigated for its potential anti-cancer effects in various types of cancer, including hepatocellular carcinoma (HCC). However, its suppressing effect on reactive oxygen species (ROS) production might limited its anti-cancer effects. In this study, we aimed to explore the interplay among quercetin, mitochondrial dynamics and mitophagy and whether mitophagy-inhibition synergistically enhances the anti-tumor effects of quercetin. Huh7 and Hep3B cells were utilized for in vitro and in vivo studies. Results showed that quercetin treatment significantly increased the expression of mitochondrial fusion genes (MFN1 and MFN2) and decreased the expression of fission genes (DRP1 and FIS1) in Huh7 and Hep3B cells, leading to a more fused and elongated mitochondrial network. Quercetin upregulated the expression of key mitophagy regulators, PINK1 and PARK2, and enhanced the colocalization of mitochondria with lysosomes, indicating increased mitophagy. Knockdown of PINK1, PARK2, or SIRT1 attenuated quercetin-induced mitophagy and reduction of intracellular ROS levels. Quercetin treatment upregulates SIRT1 expression, which subsequently enhances PINK1 and PARK2 expression in Huh7 and Hep3B cells. In vivo experiments using Hep3B xenograft models revealed that the combination of quercetin with the mitophagy inhibitor hydroxychloroquine or SIRT1 knockdown significantly enhanced the anticancer effects of quercetin, as evidenced by reduced tumor size and weight, increased necrosis and apoptosis, and decreased proliferation in tumor tissues. These findings suggest that quercetin-induced mitochondrial fusion and Pink1/Parkin-dependent mitophagy may negatively influence its anti-cancer effects in HCC. Targeting mitophagy may enhance the therapeutic potential of quercetin in HCC treatment.

Keywords:  Hepatocellular carcinoma; Mitophagy; Park2; Pink1; Quercetin

DOI:  https://doi.org/10.1016/j.bbrc.2024.149899
Autophagy. 2024 Apr 23. 1-12

The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.

Simone Patergnani, Méghane S Bataillard, Alberto Danese, Stacy Alves, Chantal Cazevieille, René Valéro, Lisbeth Tranebjærg, Tangui Maurice, Paolo Pinton, Benjamin Delprat, Elodie M Richard.

  Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

Keywords:  Autophagy; WFS1; Wolfram-like syndrome; mitochondria-associated endoplasmic reticulum membrane; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2341588
Nat Commun. 2024 Apr 20. 15(1): 3375

Inflammation and mitophagy are mitochondrial checkpoints to aging.

Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.

DOI: https://doi.org/10.1038/s41467-024-47840-1
Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.

  Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy

DOI:  https://doi.org/10.1186/s11658-024-00572-y
Transl Res. 2024 Apr 19. pii: S1931-5244(24)00079-3. [Epub ahead of print]

Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.

Yang Li, Boqing Dong, Ying Wang, Huanjing Bi, Jing Zhang, Chenguang Ding, Chenge Wang, Xiaoming Ding, Wujun Xue.

  Mitochondrial dysfunction is recognized as a pivotal contributor to the pathogenesis of renal ischemia-reperfusion (IR) injury. Mitophagy, the process responsible for removing damaged protein aggregates, stands as a critical mechanism safeguarding cells against IR injury. Currently, the role of deubiquitination in regulating mitophagy still needs to be completely elucidated. This study aimed to evaluate the impact of ubiquitin-specific peptidase 14 (Usp14), a deubiquitinase, in IR injury by influencing mitophagy. Utilizing a murine model of renal IR injury, Usp14 silencing was found to ameliorate kidney injury, leading to decreased levels of serum creatinine and blood urea nitrogen, alongside diminished oxidative stress and inflammation. In renal epithelial cells subjected to hypoxia/reoxygenation (H/R), Usp14 knockdown increased cell viability and reduced apoptosis. Further mechanistic studies revealed that Usp14 interacted with and deubiquitinated transcription factor AP-2 alpha (Tfap2a), thereby suppressing its downstream target gene, TANK binding kinase 1 (Tbk1), to influence mitophagy. Tfap2a overexpression or Tbk1 inhibition reversed the protective effects of Usp14 silencing on renal tubular cell injury and its facilitation of mitophagy. In summary, our study demonstrated the renoprotective role of Usp14 knockdown in mitigating renal IR injury by promoting Tfap2a-mediated Tbk1 upregulation and mitophagy. These findings advocate for exploring Usp14 inhibition as a promising therapeutic avenue for mitigating IR injury, primarily by enhancing the clearance of damaged mitochondria through augmented mitophagy.

Keywords:  Mitophagy; Oxidative stress; Renal ischemia/reperfusion injury; Ubiquitin-specific protease 14

DOI:  https://doi.org/10.1016/j.trsl.2024.04.002
J Mater Chem B. 2024 Apr 23.

A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.

Deeksha Rajput, Nachiket Pradhan, Shabnam Mansuri, Virupakshi Soppina, Sriram Kanvah.

This paper explores the use of a di-cationic fluorophore for visualizing mitochondria in live cells independent of membrane potential. Through the synthesized di-cationic fluorophore, we investigate the monitoring of viscosity, ferroptosis, stress-induced mitophagy, and lysosomal uptake of damaged mitochondria. The designed fluorophore is based on DQAsomes, cationic vesicles responsible for transporting drugs and DNA to mitochondria. The symmetric fluorophores possess two charge centres separated by an alkyl chain and are distinguished by a pyridinium group for mitochondrial selectivity, the C-12 alkyl substitution for membrane affinity, and an electron donor-π-acceptor fluorescent scaffold for intramolecular charge transfer. The synthesized fluorophores, PP and NP, emit wavelengths exceeding 600 nm, with a significant Stokes shift (130-211 nm), and NP demonstrates near-infrared emission (∼690 nm). Our study underscores the potential of these fluorophores for live-cell imaging, examining physiological responses such as viscosity and ferroptosis, and highlights their utility in investigating mitophagy damage and lysosomal uptake.

DOI: https://doi.org/10.1039/d4tb00293h
PLoS Biol. 2024 Apr 26. 22(4): e3002602

Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.

Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.

Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

DOI: https://doi.org/10.1371/journal.pbio.3002602
Microorganisms. 2024 Apr 17. pii: 813. [Epub ahead of print]12(4):

Contribution of the Type III Secretion System (T3SS2) of Vibrio parahaemolyticus in Mitochondrial Stress in Human Intestinal Cells.

Nicolás Plaza, Diliana Pérez-Reytor, Gino Corsini, Katherine García, Ítalo M Urrutia.

  Vibrio parahaemolyticus is an important human pathogen that is currently the leading cause of shellfish-borne gastroenteritis in the world. Particularly, the pandemic strain has the capacity to induce cytotoxicity and enterotoxicity through its Type 3 Secretion System (T3SS2) that leads to massive cell death. However, the specific mechanism by which the T3SS2 induces cell death remains unclear and its contribution to mitochondrial stress is not fully understood. In this work, we evaluated the contribution of the T3SS2 of V. parahaemolyticus in generating mitochondrial stress during infection in human intestinal HT-29 cells. To evaluate the contribution of the T3SS2 of V. parahaemolyticus in mitochondrial stress, infection assays were carried out to evaluate mitochondrial transition pore opening, mitochondrial fragmentation, ATP quantification, and cell viability during infection. Our results showed that the Δvscn1 (T3SS2+) mutant strain contributes to generating the sustained opening of the mitochondrial transition pore. Furthermore, it generates perturbations in the ATP production in infected cells, leading to a significant decrease in cell viability and loss of membrane integrity. Our results suggest that the T3SS2 from V. parahaemolyticus plays a role in generating mitochondrial stress that leads to cell death in human intestinal HT-29 cells. It is important to highlight that this study represents the first report indicating the possible role of the V. parahaemolyticus T3SS2 and its effector proteins involvement in generating mitochondrial stress, its impact on the mitochondrial pore, and its effect on ATP production in human cells.

Keywords:  T3SS2; Vibrio parahaemolyticus; cell death; foodborne illness; mitochondria

DOI:  https://doi.org/10.3390/microorganisms12040813
Nat Cell Biol. 2024 Apr 23.

Regulation of mitochondrial fission by fatty acyl-coenzyme A.

DOI: https://doi.org/10.1038/s41556-024-01406-x
Curr Biol. 2024 Apr 17. pii: S0960-9822(24)00390-7. [Epub ahead of print]

Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.

Alice Pavlowsky, Typhaine Comyn, Julia Minatchy, David Geny, Philippe Bun, Lydia Danglot, Thomas Preat, Pierre-Yves Plaçais.

  Neurons have differential and fluctuating energy needs across distinct cellular compartments, shaped by brain electrochemical activity associated with cognition. In vitro studies show that mitochondria transport from soma to axons is key to maintaining neuronal energy homeostasis. Nevertheless, whether the spatial distribution of neuronal mitochondria is dynamically adjusted in vivo in an experience-dependent manner remains unknown. In Drosophila, associative long-term memory (LTM) formation is initiated by an early and persistent upregulation of mitochondrial pyruvate flux in the axonal compartment of neurons in the mushroom body (MB). Through behavior experiments, super-resolution analysis of mitochondria morphology in the neuronal soma and in vivo mitochondrial fluorescence recovery after photobleaching (FRAP) measurements in the axons, we show that LTM induction, contrary to shorter-lived memories, is sustained by the departure of some mitochondria from MB neuronal soma and increased mitochondrial dynamics in the axonal compartment. Accordingly, impairing mitochondrial dynamics abolished the increased pyruvate consumption, specifically after spaced training and in the MB axonal compartment, thereby preventing LTM formation. Our results thus promote reorganization of the mitochondrial network in neurons as an integral step in elaborating high-order cognitive processes.

Keywords:  3D-STED microscopy; Drosophila; brain energy metabolism; long-term memory; mitochondria motility; mushroom body

DOI:  https://doi.org/10.1016/j.cub.2024.03.050
FEBS Open Bio. 2024 Apr 25.

Protein insertion into the inner membrane of mitochondria: routes and mechanisms.

Büsra Kizmaz, Annika Nutz, Annika Egeler, Johannes M Herrmann.

  The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

Keywords:  TIM22 complex; TIM23 complex; carrier proteins; membrane proteins; mitochondria; protein import

DOI:  https://doi.org/10.1002/2211-5463.13806
J Hazard Mater. 2024 Apr 20. pii: S0304-3894(24)00898-7. [Epub ahead of print]471 134319

18β-Glycyrrhetinic acid protects against deoxynivalenol-induced liver injury via modulating ferritinophagy and mitochondrial quality control.

Junze Jiang, Xintong Zhou, Hao Chen, Xin Wang, Yongbao Ruan, Xiaohui Liu, Jun Ma.

  Deoxynivalenol (DON), a widespread mycotoxin, represents a substantial public health hazard due to its propensity to contaminate agricultural produce, leading to both acute and chronic health issues in humans and animals upon consumption. The role of ferroptosis in DON-induced hepatic damage remains largely unexplored. This study investigates the impact of 18β-glycyrrhetinic acid (GA), a prominent constituent of glycyrrhiza, on DON hepatotoxicity and elucidates the underlying mechanisms. Our results indicate that GA effectively attenuates liver injury inflicted by DON. This was achieved by inhibiting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis, as well as by adjusting mitochondrial quality control (MQC). Specifically, GA curtails ferritinophagy by diminishing NCOA4 expression without affecting the autophagic flux. At a molecular level, GA binds to and stabilizes programmed cell death protein 4 (PDCD4), thereby inhibiting its ubiquitination and subsequent degradation. This stabilization of PDCD4 leads to the downregulation of NCOA4 via the JNK-Jun-NCOA4 axis. Knockdown of PDCD4 weakened GA's protective action against DON exposure. Furthermore, GA improved mitochondrial function and limited excessive mitophagy and mitochondrial division induced by DON. Disrupting GA's modulation of MQC nullified its anti-ferroptosis effects. Overall, GA offers protection against DON-induced ferroptosis by blocking ferritinophagy and managing MQC. ENVIRONMENTAL IMPLICATION: Food contamination from mycotoxins, is a problem for agricultural and food industries worldwide. Deoxynivalenol (DON), the most common mycotoxins in cereal commodities. A survey in 2023 showed that the positivity rate for DON contamination in food reached more than 70% globally. DON can damage the health of humans whether exposed to high doses for short periods of time or low doses for long periods of time. We have discovered 18β-Glycyrrhetinic acid (GA), a prominent constituent of glycyrrhiza. Liver damage caused by low-dose DON can be successfully treated with GA. This study will support the means of DON control, including antidotes.

Keywords:  Autophagy; Deoxynivalenol; Ferritinophagy; Ferroptosis; Glycyrrhetinic acid

DOI:  https://doi.org/10.1016/j.jhazmat.2024.134319
Res Sq. 2024 Apr 10. pii: rs.3.rs-4178088. [Epub ahead of print]

Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.

Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion ( B β 2 KO) nor fission ( Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

DOI: https://doi.org/10.21203/rs.3.rs-4178088/v1
Ecotoxicol Environ Saf. 2024 Apr 24. pii: S0147-6513(24)00439-1. [Epub ahead of print]277 116363

Aflatoxin B1-exposed hepatocyte-derived extracellular vesicles: Initiating hepatic stellate cell-mediated liver fibrosis through a p53-Parkin-dependent mitophagy pathway.

Lei Yang, Yun-Lu Gao, Shan Jiang, Bo Qian, Lin Che, Jia-Shen Wu, Ze-Bang Du, Ming-Zhu Wang, Yun Yang, Yu-Chun Lin, Gang Liu, Zhong-Ning Lin.

  Environmental aflatoxin B1 (AFB1) exposure has been proposed to contribute to hepatocellular carcinoma by promoting liver fibrosis, but the potential mechanisms remain to be further elucidated. Extracellular vesicles (EVs) were recognized as crucial traffickers for hepatic intercellular communication and play a vital role in the pathological process of liver fibrosis. The AFB1-exposed hepatocyte-derived EVs (AFB1-EVs) were extracted, and the functional effects of AFB1-EVs on the activation of hepatic stellate cells (HSCs) were explored to investigate the molecular mechanism of AFB1 exposure-induced liver fibrogenesis. Our results revealed that an environment-level AFB1 exposure induced liver fibrosis via HSCs activation in mice, while the AFB1-EVs mediated hepatotoxicity and liver fibrogenesis in vitro and in vivo. AFB1 exposure in vitro increased PINK1/Parkin-dependent mitophagy in hepatocytes, where upregulated transcription of the PARK2 gene via p53 nuclear translocation and mitochondrial recruitment of Parkin, and promoted AFB1-EVs-mediated mitochondria-trafficking communication between hepatocytes and HSCs. The knockdown of Parkin in HepaRG cells reversed HSCs activation by blocking the mitophagy-related AFB1-EVs trafficking. This study further revealed that the hepatic fibrogenesis of AFB1 exposure was rescued by genetic intervention with siPARK2 or p53's Pifithrin-α (PFTα) inhibitors. Furthermore, AFB1-EVs-induced HSCs activation was relieved by GW4869 pharmaceutic inhibition of EVs secretion. These results revealed a novel mechanism that AFB1 exposure-induced p53-Parkin signal axis regulated mitophagy-dependent hepatocyte-derived EVs to mediate the mitochondria-trafficking intercellular communication between hepatocytes and HSCs in the local hepatotoxic microenvironment to promote the activated HSCs-associated liver fibrogenesis. Our study provided insight into p53-Parkin-dependent pathway regulation and promised an advanced strategy targeting intervention to EVs-mediated mitochondria trafficking for preventing xenobiotics-induced liver fibrosis.

Keywords:  Aflatoxin B(1); Extracellular vesicles; Intercellular communications; Liver fibrogenesis; Mitochondria trafficking; p53-Parkin-dependent mitophagy

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116363
Research (Wash D C). 2024 ;7 0325

Erratum to "PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance".

Rongjun Zou, Jun Tao, Jie He, Chaojie Wang, Songtao Tan, Yu Xia, Xing Chang, Ruibing Li, Ge Wang, Hao Zhou, Xiaoping Fan.

[This corrects the article DOI: 10.34133/research.0001.].

DOI: https://doi.org/10.34133/research.0325
Ecotoxicol Environ Saf. 2024 Apr 19. pii: S0147-6513(24)00390-7. [Epub ahead of print]277 116314

HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons.

Xiaolan Li, Qin Ran, Xiang He, Dan Peng, Anying Xiong, Manling Jiang, Lei Zhang, Junyi Wang, Lingling Bai, Shengbin Liu, Shiyue Li, Baoqing Sun, Guoping Li.

  Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism-related protein Heme Oxygenase 1 (HO-1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO-1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO-1 promotes the release of excess iron, genetically inhibiting the upregulation of HO-1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO-1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.

Keywords:  Ferroptosis; HO-1; Mitophagy; Neurotoxicity; PM2.5

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116314
Science. 2024 Apr 26. 384(6694): 438-446

Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.

Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.

DOI: https://doi.org/10.1126/science.adk1005
J Appl Toxicol. 2024 Apr 20.

Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials.

Rui Zhang, Haitao Yang, Menghao Guo, Shuyan Niu, Yuying Xue.

  Mitophagy is a selective cellular process critical for the removal of damaged mitochondria. It is essential in regulating mitochondrial number, ensuring mitochondrial functionality, and maintaining cellular equilibrium, ultimately influencing cell destiny. Numerous pathologies, such as neurodegenerative diseases, cardiovascular disorders, cancers, and various other conditions, are associated with mitochondrial dysfunctions. Thus, a detailed exploration of the regulatory mechanisms of mitophagy is pivotal for enhancing our understanding and for the discovery of novel preventive and therapeutic options for these diseases. Nanomaterials have become integral in biomedicine and various other sectors, offering advanced solutions for medical uses including biological imaging, drug delivery, and disease diagnostics and therapy. Mitophagy is vital in managing the cellular effects elicited by nanomaterials. This review provides a comprehensive analysis of the molecular mechanisms underpinning mitophagy, underscoring its significant influence on the biological responses of cells to nanomaterials. Nanoparticles can initiate mitophagy via various pathways, among which the PINK1-Parkin pathway is critical for cellular defense against nanomaterial-induced damage by promoting mitophagy. The role of mitophagy in biological effects was induced by nanomaterials, which are associated with alterations in Ca2+ levels, the production of reactive oxygen species, endoplasmic reticulum stress, and lysosomal damage.

Keywords:  PINK1‐Parkin pathway; cellular responses; mitophagy; nanomaterials; regulatory mechanisms

DOI:  https://doi.org/10.1002/jat.4609
Exp Neurol. 2024 Apr 24. pii: S0014-4886(24)00124-9. [Epub ahead of print] 114798

Adenylate kinase 4 promotes neuronal energy metabolism and mitophagy in early cerebral ischemia via Parkin/PKM2 pathway.

Yunxue Zhong, Bingbing Jia, Cong Xie, Hu Linghui, Zijun Liao, Wenlan Liu, Yuan Zhang, Guodong Huang.

  Mitochondrial dysfunction is closely related to brain injury and neurological dysfunction in ischemic stroke. Adenylate kinase 4 (AK4) plays a critical role in energy metabolism and mitochondrial homeostasis. However, the underlying mechanisms remain unclear. In the present study, we demonstrated an important role of AK4 in mitochondrial dysfunction in the early cerebral ischemia. Early focal cerebral ischemia induced decrease of AK4 protein expression in ischemic hemispheric brain tissue in mice. Exposure of cultured primary neuron to oxygen-glucose deprivation (OGD) also induced AK4 downregulation. Overexpression of AK4 in neuron using adeno-associated virus (AAV-AK4) in mice promoted neuronal survival reflected by decreased infarction volume and TUNEL staining. AK4 overexpression inhibited mitochondrial decline and downregulation of energy metabolism-associated proteins (p-AMPK and ATP1A3) induced by MCAO. Moreover, AK4 knock-in using lentivirus carried AK4 vector (LV-AK4) induced energy metabolism shift from glycolysis to oxidation in neuron. Using transmission electron microscope and western blot, we revealed that AK4 overexpression promoted mitophagy and mitophagy-associated proteins expression PINK1 and Parkin after MCAO. Mass spectrometry and co-immunoprecipitation revealed an interaction between AK4 and PKM2. Mechanistically, AK4 indirectly decreased PKM2 expression via enhancing its ubiquitination by increasing the interaction between PKM2 and its ubiquitin E3 ligase Parkin, and inhibits Parkin downregulation. In conclusion, our data demonstrate that AK4/ Parkin /PKM axis prevents cerebral ischemia damage via regulation of neuronal energy metabolism model and mitophagy. AK4 was a new target for intervention of early ischemic neuron injury.

Keywords:  Adenylate kinase 4; Cerebral ischemia; Mitophagy; Pyruvate kinase M; Ubiquitination

DOI:  https://doi.org/10.1016/j.expneurol.2024.114798
Nanomaterials (Basel). 2024 Apr 17. pii: 689. [Epub ahead of print]14(8):

Mitochondrial Fission in Nickel Nanoparticle-Induced Reproductive Toxicity: An In Vitro GC-1 Cell Study.

Hanyue Zheng, Geyu Liang, Chunliu Guan, Lin Liu, Jiahui Dong, Jinshun Zhao, Meng Tang, Lu Kong.

  Reproductive disorders and declining fertility rates are significant public health concerns affecting birth rates and future populations. Male infertility, often due to spermatogenesis defects, may be linked to environmental pollutants like nickel nanoparticles (Ni NPs). Ni NPs are extensively utilized across different industries. Nevertheless, their potential adverse effects cannot be overlooked. Previous studies have linked the reproductive toxicity induced by Ni NPs with disturbances in mitochondrial function. Mitochondrial division/fusion dynamics are crucial to their proper function, yet little is known about how Ni NPs perturb these dynamics and whether such perturbation contributes to the impairment of the male reproductive system. Herein, we demonstrated that the exposure of Ni NPs to the mouse-derived spermatogonia cell line (GC-1 cells) triggered DRP1-mediated mitochondrial division and the enhanced impairment of mitochondria, consequently promoting mitochondria-dependent cell apoptosis. Notably, both the mitochondrial division inhibitor (Mdivi-1) and lentiviral-transfected cells with low expression of Dnm1l-DK in these cells could mitigate the toxic effects induced by Ni NPs, pointing to the potential role of mitochondrial dynamics in Ni NP-induced reproductive toxicity. Collectively, our work contributes to the understanding of the mechanisms by which Ni NPs can impact male reproductive function and identifies mitochondrial division as a potential target for intervention.

Keywords:  GC-1 cell; apoptosis; environmental pollutant; mitochondrial division; nickel nanoparticle; reproductive toxicity

DOI:  https://doi.org/10.3390/nano14080689
Sci Total Environ. 2024 Apr 21. pii: S0048-9697(24)02802-X. [Epub ahead of print] 172655

Low-dose BPA-induced neuronal energy metabolism dysfunction and apoptosis mediated by PINK1/parkin mitophagy pathway in juvenile rats.

Lingxue Meng, Zedong Ouyang, Yuxin Chen, Chengmeng Huang, Yunjiang Yu, Ruifang Fan.

  Bisphenol A (BPA) is related to neurological disorders involving mitochondrial dysfunction, while the mechanism remains elusive. Therefore, we explored it through in vitro and in vivo experiments. In vitro, hippocampal neurons derived from neonatal rats of different genders were exposed to 1-100 nM and 100 μM BPA, autophagy activator Rapa and inhibitor 3-MA for 7 d. The results suggested that even nanomolar BPA (1-100 nM) disturbed Ca2+ homeostasis and damaged the integrity of mitochondrial cristae in neurons (p < 0.05). Furthermore, BPA increased the number of autophagic lysosomes, LC3II/LC3I ratio, and p62 expression, and decreased parkin expression (p < 0.05), suggesting that the entry of damaged mitochondria into autophagic pathway was prompted, while the autophagic degradation pathway was blocked. This further disrupts neuronal energy metabolism and promotes neuronal apoptosis. However, Rapa attenuated the adverse effects caused by BPA, while 3-MA exacerbated these reactions. In vivo, exposure of juvenile rats to 0.5, 50, 5000 μg/kg‧bw/day BPA during PND 7-21 markedly impaired the structure of hippocampal mitochondria, increased the number of autophagosomes, the rate of neuronal apoptosis, and the expression levels of pro-apoptotic proteins Cyt C, Bax, Bak1, and Caspase3, and decreased the expression of anti-apoptotic protein Bcl2 (p < 0.05). Particularly, male rats are more sensitive to low-dose BPA than females. Overall, environmental-doses BPA can induce the imbalance of energy metabolism in hippocampal neurons via PINK1/parkin mitophagy, thereby inducing their apoptosis. Importantly, this study provides a theoretical basis for attenuating BPA-related neurological diseases.

Keywords:  Apoptosis; Bisphenol A; Energy metabolism; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.scitotenv.2024.172655