bims-mikwok 2023-09-24 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒09‒24
ten papers selected by
Gavin McStay, Liverpool John Moores University

Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
Mitochondrial protein and organelle quality control-Lessons from budding yeast.
Blockade of hepatocyte PCSK9 ameliorates hepatic ischemia- reperfusion injury by promoting pink1-parkin-mediated mitophagy.
Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.
Molecular basis for maternal inheritance of human mitochondrial DNA.
Folic Acid Protects against Ethanol-Induced Hepatic Mitophagy Imbalance by ROS Scavenging and Attenuating the Elevated Hcy Levels.
Protocol for real-time imaging of membrane fission by mitofissin.
Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.

Sci Adv. 2023 Sep 22. 9(38): eadh8228

Temporal landscape of mitochondrial proteostasis governed by the UPRmt.

Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.

Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.

DOI: https://doi.org/10.1126/sciadv.adh8228
IUBMB Life. 2023 Sep 20.

Mitochondrial protein and organelle quality control-Lessons from budding yeast.

Emily Jie-Ning Yang, Pin-Chao Liao, Liza Pon.

  Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.

Keywords:  ageing; mitochondria; mitochondrial reactive oxygen species; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1002/iub.2783
Cell Mol Gastroenterol Hepatol. 2023 Sep 15. pii: S2352-345X(23)00166-2. [Epub ahead of print]

Blockade of hepatocyte PCSK9 ameliorates hepatic ischemia- reperfusion injury by promoting pink1-parkin-mediated mitophagy.

Yu Zhang, Ziyi Wang, Chenyang Jia, Wenjie Yu, Xiangdong Li, Nan Xia, Huiling Nie, Pascalia Wikana Likalamu, Minhao Chen, Yong Ni, Sheng Han, Liyong Pu.

  BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury.METHODS: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion (IR) models and AML12 cells subjected to hypoxia/reoxygenation (H/R). Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response.
RESULTS: Our findings reveal that PCSK9 is upregulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy.
CONCLUSIONS: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) by promoting pink1-parkin-mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.

Keywords:  PCSK9; hepatic ischemia-reperfusion; mitophagy; pink1; sting

DOI:  https://doi.org/10.1016/j.jcmgh.2023.09.004
Neurotoxicology. 2023 Sep 16. pii: S0161-813X(23)00124-9. [Epub ahead of print]99 50-58

Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.

Wenqiong Wang, Rui Chang, Yan Wang, Liyan Hou, Qingshan Wang.

  We recently revealed a pivotal role of NLRP3 inflammasome in the neurotoxicity induced by n-hexane, owing to its activation and release of pro-inflammatory cytokines. However, the mechanisms of how the activation of NLRP3 inflammasome was triggered by 2,5-hexanedione (HD), the toxic product of n-hexane metabolism, remain to be explored. Here, we investigated whether mitochondrial reactive oxygen species (mtROS) was involved in HD-elicited NLRP3 inflammasome activation in microglia. We demonstrated that exposure to HD at 4 and 8 mM elevated production of mtROS in BV2 microglia. Scavenging mtROS by Mito-TEMPO, an mtROS scavenger, dramatically reduced HD-induced NLRP3 expression, caspase-1 activation and interleukin-1β production, pointing a crucial role of mtROS in NLRP3 inflammasome activation. Mechanistic study revealed that HD intoxication promoted activation of mitophagy. HD induced expression of Beclin-1, LC3II, and two mitophagy-related proteins, i.e., Pink1 and Parkin and simultaneously, reduced p62 expression in both whole cell and isolated mitochondria of microglia. Furthermore, inhibition of mitophagy by 3-methyladenine (3-MA) greatly reduced production of mtROS, expression of mitochondrial fission-related proteins, dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) and activation of NLRP3 inflammasome in HD-intoxicated microglia. Blocking mitochondrial fission by Mdivi-1 also prevented HD-induced mtROS production and NLRP3 inflammasome activation in microglia. In conclusion, our data indicated that HD triggered activation of NLRP3 inflammasome through mitophagy-dependent mtROS production, offering an important insight for the immunopathogenesis of environmental toxins-induced neuroinflammation and neurotoxicity.

Keywords:  Mitochondrial ROS; Mitochondrial fission; Mitophagy; N-Hexane; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.neuro.2023.09.008
PLoS Biol. 2023 Sep 18. 21(9): e3002310

Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.

Xenia Chelius, Veronika Bartosch, Nathalie Rausch, Magdalena Haubner, Jana Schramm, Ralf J Braun, Till Klecker, Benedikt Westermann.

Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.

DOI: https://doi.org/10.1371/journal.pbio.3002310
EBioMedicine. 2023 Sep 20. pii: S2352-3964(23)00375-4. [Epub ahead of print]96 104809

Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.

Catriona Ling, Christian J Versloot, Matilda E Arvidsson Kvissberg, Guanlan Hu, Nathan Swain, José M Horcas-Nieto, Emily Miraglia, Mehakpreet K Thind, Amber Farooqui, Albert Gerding, Karen van Eunen, Mirjam H Koster, Niels J Kloosterhuis, Lijun Chi, YueYing ChenMi, Miriam Langelaar-Makkinje, Celine Bourdon, Jonathan Swann, Marieke Smit, Alain de Bruin, Sameh A Youssef, Marjon Feenstra, Theo H van Dijk, Kathrin Thedieck, Johan W Jonker, Peter K Kim, Barbara M Bakker, Robert H J Bandsma.

  BACKGROUND: The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health.METHODS: SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD+-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities.
FINDINGS: LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction.
INTERPRETATION: Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials.
FUNDING: This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.

Keywords:  Autophagy; Enteropathy; Malnutrition; Mitochondria; SIRT1

DOI:  https://doi.org/10.1016/j.ebiom.2023.104809
Nat Genet. 2023 Sep 18.

Molecular basis for maternal inheritance of human mitochondrial DNA.

William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.

DOI: https://doi.org/10.1038/s41588-023-01505-9
J Agric Food Chem. 2023 Sep 22.

Folic Acid Protects against Ethanol-Induced Hepatic Mitophagy Imbalance by ROS Scavenging and Attenuating the Elevated Hcy Levels.

Huichao Zhao, Haiqi Gao, Yabin Zhang, Tongtong Lan, Jingwen Wang, Haifeng Zhao, Huaqi Zhang, Meilan Xue, Hui Liang.

  Ample evidence indicates that ethanol-induced oxidative stress and mitochondrial dysfunction are central to the pathogenesis of alcoholic liver disease (ALD). As an adaptive quality control mechanism, mitophagy removes dysfunctional mitochondria to avert hepatic lesions in ALD. Folic acid exhibits potential radical scavenging properties and has been proven to ameliorate mitochondrial disorder in oxidative stress-related diseases. In this study, we aimed to uncover the mitophagy regulatory effects of folic acid in a 10w alcohol C57BL/6J mice feeding model (56% v/v) and L02 cells model cultured with ethanol (2.5% v/v). The results showed that folic acid alleviates ethanol-induced liver injury, decreasing oxidative stress and restoring liver enzyme. Furthermore, folic acid improved the mitochondrial function and inhibited ethanol-activated mitophagy through decreasing PINK1-Parkin and Drp1 expression, which inhibited the release of mitochondrial cytochrome C to the cytoplasm, preventing hepatocyte apoptosis. Intriguingly, folic acid attenuates the elevated hepatic homocysteine (Hcy) level. Additionally, the pretreatment of L02 cells with folic acid also ameliorated Hcy-induced oxidative damage, mitochondrial fission, and mitophagy. In summary, these results suggest that folic acid has beneficial effects in mitophagy remodeling by ROS scavenging and facilitating Hcy metabolism and could be developed as a potential therapeutic agent against ALD.

Keywords:  ALD.; Hcy; L02; acid; cells; effects; ethanol-induced; folic; hepatic; inhibited; liver; mitochondrial; mitophagy; model; oxidative; potential; results; scavenging; stress

DOI:  https://doi.org/10.1021/acs.jafc.3c01851
STAR Protoc. 2023 Sep 21. pii: S2666-1667(23)00557-9. [Epub ahead of print]4(4): 102590

Protocol for real-time imaging of membrane fission by mitofissin.

Tatsuro Maruyama, Nobuo N Noda.

  Yeast mitofissin Atg44 is a mitochondrial intermembrane space protein that causes membrane fission required for mitophagy. Here, we present a protocol for observing Atg44-mediated membrane fission. We describe steps for recombinant Atg44 purification, lipid nanotube preparation as model membranes, and Atg44-mediated membrane fission real-time observation. We then detail procedures for tube radius estimation using confocal microscopy. This protocol can also be adapted to the study of membrane fission by other proteins. For complete details on the use and execution of this protocol, please refer to Fukuda et al. (2023).1.

Keywords:  Biophysics; Microscopy; Protein Biochemistry

DOI:  https://doi.org/10.1016/j.xpro.2023.102590
Sci Immunol. 2023 Sep 29. 8(87): eadf7579

Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.

Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung-Chi Kao, Chun-Pu Lin, Lorène Rousseau, Fu-Ti Peng, Yu-Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E Speiser, Federica Sallusto, Ping-Chih Ho.

Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.

DOI: https://doi.org/10.1126/sciimmunol.adf7579