bims-mikwok 2023-10-29 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–10–29
thirteen papers selected by
Gavin McStay, Liverpool John Moores University

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.
Lasmiditan restores mitochondrial quality control mechanisms and accelerates renal recovery after ischemia-reperfusion injury.
The germline coordinates mitokine signaling.
The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.
The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.
Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.
Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.
Role of Mitochondrial Dynamics in Heart Diseases.
Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.
A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease.
A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
Polystyrene nanoparticles induced mammalian intestine damage caused by blockage of BNIP3/NIX-mediated mitophagy and gut microbiota alteration.

Autophagy. 2023 Oct 24.

Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome.

Kun Gao, Yingji Chen, Ren Mo, Chenji Wang.

  Mitophagy, the process of removing damaged mitochondria to promote cell survival, plays a crucial role in cellular functionality. However, excessive, or uncontrolled mitophagy can lead to reduced mitochondrial content that burdens the remaining organelles, triggering mitophagy-mediated cell death. FBXL4 mutations, which affect the substrate-binding adaptor of the CUL1 (cullin 1)-RING ubiquitin ligase complex (CRL1), have been linked to mitochondrial DNA depletion syndrome type 13 (MTDPS13) characterized by reduced mtDNA content and impaired energy production in affected organs. However, the mechanism behind FBXL4 mutation-driven MTDPS13 remain poorly understood. In a recent study, we demonstrate that the CRL1-FBXL4 complex promotes the degradation of BNIP3 and BNIP3L, two key mitophagy cargo receptors. Deficiency of FBXL4 results in a strong accumulation of BNIP3 and BNIP3L proteins and triggers high levels of BNIP3- and BNIP3L-dependent mitophagy. Patient-derived FBXL4 mutations do not affect its interaction with BNIP3 and BNIP3L but impair the assembly of an active CRL1-FBXL4 complex. Furthermore, excessive mitophagy is observed in knockin mice carrying a patient-derived FBXL4 mutation, and in cortical neurons generated from human patient induced pluripotent stem cells (hiPSCs). These findings support the model that the CRL1-FBXL4 complex tightly restricts basal mitophagy, and its dysregulation leads to severe symptoms of MTDPS13.

Keywords:  Lysosome; mitochondria; mitophagy; multi-system disorder; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2023.2274260
Biochem Pharmacol. 2023 Oct 21. pii: S0006-2952(23)00446-X. [Epub ahead of print]218 115855

Lasmiditan restores mitochondrial quality control mechanisms and accelerates renal recovery after ischemia-reperfusion injury.

Kevin A Hurtado, Jaroslav Janda, Rick G Schnellmann.

   BACKGROUND: Mitochondrial dysfunction is a well-established result of acute kidney injury (AKI). Previously, we identified that 5-hydroxytryptamine 1F (5-HT1F) receptor agonism with lasmiditan induces mitochondrial biogenesis (MB) and improves renal vasculature and function in an AKI mouse model. We hypothesize that lasmiditan also modulates mitochondrial dynamics and mitophagy in a mouse model of AKI.
METHODS: Male mice were subjected to renal ischemia/reperfusion (I/R) and treated daily with lasmiditan (0.3 mg/kg) or vehicle beginning 24 h after injury for 3 or 6d. Serum creatinine was measured to estimate glomerular filtration. Electron microscopy was used to assess mitochondrial morphology and mitophagy. Mitochondrial-related protein were confirmed with immunoblotting. Mitochondrial function was assessed with ATP measurements.
RESULTS: Lasmiditan treatment improved mitochondrial and kidney recovery as early as 3d post-AKI, as evidenced by increased ATP, and decreased serum creatinine, respectively. Electron micrographs of renal cortices revealed that lasmiditan also decreased mitochondrial damage and increased mitochondrial area and size by 6d after I/R injury. Additionally, lasmiditan treatment increased mitolysosomes by 3d, indicating induction of mitophagy. Phosphorylation of mitophagy-related proteins were also increased in the renal cortices of lasmiditan-treated AKI mice 3d after I/R injury, whereas fusion-related proteins were increased at 6d after I/R injury.
CONCLUSION: These data reveal that lasmiditan accelerates renal recovery, restores normal mitochondrial membrane and cristae morphology, decreases excessive mitochondrial fission, and accelerates mitophagy post-AKI in a time-dependent manner, establishing mitochondrial function and recovery from AKI.

Keywords:  Acute kidney injury; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.bcp.2023.115855
bioRxiv. 2023 Oct 04. pii: 2023.08.21.554217. [Epub ahead of print]

The germline coordinates mitokine signaling.

Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Lawrence Joe, Kristen Berendzen, Andrew Dillin.

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans , neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the WNT ligand EGL-20, which activate the mitochondrial unfolded protein response (UPR MT ) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-peripheral UPR MT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, like WNT and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPR MT activation. We also find that the germline tissue itself is essential in UPR MT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

DOI: https://doi.org/10.1101/2023.08.21.554217
Nat Commun. 2023 Oct 23. 14(1): 6721

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.

Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

DOI: https://doi.org/10.1038/s41467-023-42564-0
Glia. 2023 Oct 23.

Drosophila tweety facilitates autophagy to regulate mitochondrial homeostasis and bioenergetics in Glia.

Ho Hang Leung, Christina Mansour, Morgan Rousseau, Anwar Nakhla, Kirill Kiselyov, Kartik Venkatachalam, Ching-On Wong.

  Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected. Here, we identify an endolysosomal membrane protein that facilitates autophagy to regulate ATP production in glia. We determined that Drosophila tweety (tty) is highly expressed in glia and localized to endolysosomes. Diminished fusion between autophagosomes and endolysosomes in tty-deficient glia was rescued by expressing the human Tweety Homolog 1 (TTYH1). Loss of tty in glia attenuated mitochondrial turnover, elevated mitochondrial oxidative stress, and impaired locomotor functions. The cellular and organismal defects were partially reversed by antioxidant treatment. We performed live-cell imaging of genetically encoded metabolite sensors to determine the impact of tty and autophagy deficiencies on glial bioenergetics. We found that tty-deficient glia exhibited reduced mitochondrial pyruvate consumption accompanied by a shift toward glycolysis for ATP production. Likewise, genetic inhibition of autophagy in glia resulted in a similar glycolytic shift in bioenergetics. Furthermore, the survival of mutant flies became more sensitive to starvation, underlining the significance of tty in the crosstalk between autophagy and bioenergetics. Together, our findings uncover the role for tty in mitochondrial homeostasis via facilitating autophagy, which determines bioenergetic balance in glia.

Keywords:  Drosophila; autophagy; bioenergetics; endolysosomes; mitochondria; tweety homologs

DOI:  https://doi.org/10.1002/glia.24484
Autophagy. 2023 Oct 24.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Yu Song, Huaizhen Liang, Gaocai Li, Liang Ma, Dingchao Zhu, Weifeng Zhang, Bide Tong, Shuai Li, Yong Gao, Xinghuo Wu, Yukun Zhang, Xiaobo Feng, Kun Wang, Cao Yang.

  Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.

Keywords:  Intervertebral disc degeneration; NLRX1; SLC39A7; mitochondrial dynamics; mitophagy; nucleus pulposus

DOI:  https://doi.org/10.1080/15548627.2023.2274205
J Biol Chem. 2023 Oct 20. pii: S0021-9258(23)02408-0. [Epub ahead of print] 105380

Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.

Kelsey A Nolden, Megan C Harwig, R Blake Hill.

  Mitochondrial Fission Protein 1 (Fis1) and Dynamin Related Protein 1 (Drp1) are the only two proteins evolutionarily conserved for mitochondrial fission, and directly interact in S. cerevisiae to facilitate membrane scission. However, it remains unclear if a direct interaction is conserved in higher eukaryotes as other Drp1 recruiters, not present in yeast, are known. Using NMR, differential scanning fluorimetry, and microscale thermophoresis, we determined that human Fis1 directly interacts with human Drp1 (KD = 12-68 μM), and appears to prevent Drp1 assembly, but not GTP hydrolysis. Similar to yeast, the Fis1-Drp1 interaction appears governed by two structural features of Fis1: its N-terminal arm and a conserved surface. Alanine scanning mutagenesis of the arm identified both loss- and gain-of-function alleles with mitochondrial morphologies ranging from highly elongated (N6A) to highly fragmented (E7A) demonstrating a profound ability of Fis1 to govern morphology in human cells. An integrated analysis identified a conserved Fis1 residue, Y76, that upon substitution to alanine, but not phenylalanine, also caused highly fragmented mitochondria. The similar phenotypic effects of the E7A and Y76A substitutions, along with NMR data, support that intramolecular interactions occur between the arm and a conserved surface on Fis1 to promote Drp1-mediated fission as in S. cerevisiae. These findings indicate that some aspects of Drp1-mediated fission in humans derive from direct Fis1-Drp1 interactions that are conserved across eukaryotes.

Keywords:  biophysics; cell biology; confocal microscopy; fission; microscale thermophoresis (MST); mitochondria; mitochondrial dynamics; nuclear magnetic resonance (NMR); protein-protein interaction

DOI:  https://doi.org/10.1016/j.jbc.2023.105380
FASEB J. 2023 11;37(11): e23265

Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.

Qianqian Yang, Lulu Wang, Yuehong Liang, Qingyu He, Qi Sun, Jing Luo, Hongdi Cao, Yi Fang, Yang Zhou, Junwei Yang, Ping Wen, Lei Jiang.

  Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

Keywords:  OMA1; OPA1; UCP2; mitochondria; podocyte injury

DOI:  https://doi.org/10.1096/fj.202301055R
Genes (Basel). 2023 Sep 26. pii: 1876. [Epub ahead of print]14(10):

Role of Mitochondrial Dynamics in Heart Diseases.

Takeshi Tokuyama, Shigeru Yanagi.

  Mitochondrial dynamics, including fission and fusion processes, are essential for heart health. Mitochondria, the powerhouses of cells, maintain their integrity through continuous cycles of biogenesis, fission, fusion, and degradation. Mitochondria are relatively immobile in the adult heart, but their morphological changes due to mitochondrial morphology factors are critical for cellular functions such as energy production, organelle integrity, and stress response. Mitochondrial fusion proteins, particularly Mfn1/2 and Opa1, play multiple roles beyond their pro-fusion effects, such as endoplasmic reticulum tethering, mitophagy, cristae remodeling, and apoptosis regulation. On the other hand, the fission process, regulated by proteins such as Drp1, Fis1, Mff and MiD49/51, is essential to eliminate damaged mitochondria via mitophagy and to ensure proper cell division. In the cardiac system, dysregulation of mitochondrial dynamics has been shown to cause cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and various cardiac diseases, including metabolic and inherited cardiomyopathies. In addition, mitochondrial dysfunction associated with oxidative stress has been implicated in atherosclerosis, hypertension and pulmonary hypertension. Therefore, understanding and regulating mitochondrial dynamics is a promising therapeutic tool in cardiac diseases. This review summarizes the role of mitochondrial morphology in heart diseases for each mitochondrial morphology regulatory gene, and their potential as therapeutic targets to heart diseases.

Keywords:  Drp1; Mfn1; Mfn2; Opa1; cardiovascular diseases; fission and fusion; heart failure; mitochondrial dynamics

DOI:  https://doi.org/10.3390/genes14101876
Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00336-7. [Epub ahead of print]

Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.

Alexia Pearah, Balamurugan Ramatchandirin, Ting Liu, Risa M Wolf, Arisa Ikeda, Sally Radovick, Hiromi Sesaki, Fredric E Wondisford, Brian O'Rourke, Ling He.

  Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.

Keywords:  AKT; AMPK targeting peptides; AMPKαS496 phosphorylation; PKA; hyperglycemia; liver gluconeogenesis; mitochondrial fission

DOI:  https://doi.org/10.1016/j.chembiol.2023.09.017
Int J Biol Macromol. 2023 Oct 19. pii: S0141-8130(23)04463-X. [Epub ahead of print] 127566

A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease.

Hsuan-Hsuan Lo, Ya-Jyun Chen, Cheng-Han Jiang, Chih-Hua Tseng, Chia-Ning Yang.

  The serine/threonine kinase PINK1 is responsible for phosphorylating a ubiquitin (Ub)-like domain in an E3 Ub ligase Parkin protein and a Parkin-bound Ub. PINK1 works as a mitochondrial quality control by phosphorylating and activating the E3 ubiquitin ligase Parkin. Recent medicinal study has reported that mutations of Parkin and PINK1 cause defects in mitophagy and induce early-onset Parkinson's disease (EOPD). In this study, we conducted molecular dynamics simulations to investigate the structural discrepancy caused by a clinical G409V mutation in PINK1 kinase domain's A-loop. The Ub phosphorylation begins with PINK1 D362 deprotonating the hydroxyl group of the substrate Ub's S65' and PINK1's A-loop is responsible for coordinating S65'. On contrary to G409 offering structural plasticity, the replaced, bulky V409 interferes with the alignment of D362-S65', seriously hampering Ub phosphorylation, leading to the accumulation of damaged mitochondria, and ultimately EOPD. In this study, we predicted the hPINK1WT-UbWT binding mode and detected the structural impact brought by G409V replacement. It is expected the concluded remarks to be beneficial for developing cures to alleviate structural interference and restore PINK1 function.

Keywords:  Early-onset Parkinson's disease; Molecular dynamics simulations; PINK1

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127566
bioRxiv. 2023 Oct 04. pii: 2023.10.03.560745. [Epub ahead of print]

A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.

Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.

Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial inner membrane-localized MICOS complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe , a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS complexes to promote normal mitochondrial morphology and respiratory function. Bioinformatic analyses reveal that Mmc1 is a distant relative of the Dynamin-Related Protein (DRP) family of GTPases, which are well established to shape and remodel membranes. We find that, like DRPs, Mmc1 self-associates and forms high molecular weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting it does not dynamically remodel membranes. These data are consistent with a model in which Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.

DOI: https://doi.org/10.1101/2023.10.03.560745
Sci Total Environ. 2023 Oct 24. pii: S0048-9697(23)06691-3. [Epub ahead of print] 168064

Polystyrene nanoparticles induced mammalian intestine damage caused by blockage of BNIP3/NIX-mediated mitophagy and gut microbiota alteration.

Yilun Zhang, Zhenzhen Jia, Xianlei Gao, Juan Zhao, Hongyan Zhang.

  Nanoplastics possess the capacity for cellular internalization, and consequentially disrupt mitochondrial functionality, precipitating aberrations in energy metabolism. Given this, the potential accumulation of nanoplastics in alimentary sources presents a considerable hazard to the mammalian gastrointestinal system. While mitophagy serves as a cytoprotective mechanism that sustains redox homeostasis through the targeted removal of compromised mitochondria, the regulatory implications of mitophagy in nanoplastic-induced toxicity remain an underexplored domain. In the present investigation, polystyrene (PS) nanoparticles, with a diameter of 80 nm employed as a representative model to assess their toxicological impact and propensity to instigate mitophagy in intestinal cells both in vitro and in vivo. Data indicated that PS nanoparticles elicited BNIP3/NIX-mediated mitophagy within the intestinal milieu. Strikingly, the impediment of this degradation process at elevated concentrations was correlated with exacerbated pathological ramifications. In vitro assays corroborated that high-dosage cellular uptake of PS nanoparticles obstructed the mitophagy pathway. Furthermore, treatment with PS nanoparticles engendered alterations in gut microbiota composition and manifested a proclivity to modulate nutritional metabolism. Collectively, these findings elucidate that oral exposure to PS nanoparticles culminates in the inhibition of mitophagy and induces perturbations in the intestinal microbiota. This contributes valuable insights into the toxicological repercussions of nanoplastics on mammalian gastrointestinal health.

Keywords:  Gut microbiota; Intestinal toxicity; Mitophagy; Polystyrene nanoparticles

DOI:  https://doi.org/10.1016/j.scitotenv.2023.168064