bims-mikwok 2023-07-23 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–07–23
ten papers selected by
Gavin McStay, Liverpool John Moores University

Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.
Melatonin Promotes Mitochondrial Biogenesis and Mitochondrial Degradation in Hepatocytes During Sepsis.
Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
The mitophagy receptor NIX induces vIRF-1 oligomerization and interaction with GABARAPL1 for the promotion of HHV-8 reactivation-induced mitophagy.
DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction.
Type 1 diabetes mellitus: Inflammation, mitophagy, and mitochondrial function.
Hypoxia-induced mitochondrial stress granules.

Nat Commun. 2023 07 19. 14(1): 4356

Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.

Luis Rios, Suman Pokhrel, Sin-Jin Li, Gwangbeom Heo, Bereketeab Haileselassie, Daria Mochly-Rosen.

The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

DOI: https://doi.org/10.1038/s41467-023-40043-0
bioRxiv. 2023 Jul 07. pii: 2023.07.07.548169. [Epub ahead of print]

Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.

Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
SUMMARY: Wilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.

DOI: https://doi.org/10.1101/2023.07.07.548169
Autophagy. 2023 Jul 16.

Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.

Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Nobuo N Noda, Tomotake Kanki.

  Mitophagy is a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation. During mitophagy, specific selective autophagy receptors (SARs) mark a portion of mitochondria to recruit the autophagy-related (Atg) machinery and nucleate a phagophore. The phagophore expands and surrounds the mitochondrial cargo, forming an autophagosome. Fission plays a crucial role in separating the targeted portion of mitochondria from the main body to sequester it within the autophagosome. Our recent study, utilizing fission and budding yeasts as model systems, has identified Atg44 as a mitochondrial fission factor that generates mitochondrial fragments suitable for phagophore engulfment. Atg44 resides in the mitochondrial intermembrane space (IMS) and interacts with lipid membranes, with the capacity of mediating membrane fragility and fission. Based on our findings, we propose the term mitofissin to refer to Atg44 and its homologous proteins, which might participate in diverse cellular processes requiring membrane remodeling across various species.

Keywords:  Atg44; autophagy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast

DOI:  https://doi.org/10.1080/15548627.2023.2237343
Prog Retin Eye Res. 2023 Jul 15. pii: S1350-9462(23)00044-7. [Epub ahead of print]96 101205

Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.

Juan Ignacio Jiménez-Loygorri, Rocío Benítez-Fernández, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Beatriz Villarejo-Zori, Raquel Gómez-Sintes, Patricia Boya.

  Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.

Keywords:  Age-related macular degeneration; Autophagy; Diabetic retinopathy; Glaucoma; Metabolism; Mitochondria; Mitophagy; Retinal development; Retinal homeostasis; Retinitis pigmentosa

DOI:  https://doi.org/10.1016/j.preteyeres.2023.101205
Altern Ther Health Med. 2023 Jul 21. pii: AT8173. [Epub ahead of print]

Melatonin Promotes Mitochondrial Biogenesis and Mitochondrial Degradation in Hepatocytes During Sepsis.

Bin Hu, Zhijiang Chen, Lili Liang, Meiyu Zheng, Xinxin Chen, Qiyi Zeng.

Objective: This study aimed to investigate the protective mechanisms of melatonin in an in vitro model of sepsis-induced hepatocyte injury, specifically focusing on mitophagy and mitochondrial biogenesis.
Methods: In this study, we utilized lipopolysaccharide (LPS)-treated AML12 cells to establish an in vitro model of sepsis-induced hepatocyte injury. The effects of melatonin pretreatment were examined through various analyses, including assessments of oxidative stress, inflammation, mitophagy, mitochondrial biogenesis, and adenosine triphosphate (ATP) levels.
Results: The results revealed that LPS-treated AML12 cells exhibited elevated levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 protein, intracellular reactive oxygen species (ROS), and lipid peroxidation, specifically malondialdehyde (MDA). Moreover, the levels of key markers associated with mitophagy, including PTEN-induced putative kinase 1 (PINK1), parkin, and LC3, were significantly increased (P < .05). Similarly, markers of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM), were also significantly increased (P < .05). Conversely, superoxide dismutase (SOD) activity and ATP levels were significantly decreased in LPS-treated AML12 cells compared to the control group (P < .05). However, melatonin pretreatment led to a significant decrease in TNF-α and IL-6 protein levels, intracellular ROS, and MDA levels (P < .05), along with a significant increase in SOD activity, ATP levels, and markers of mitophagy and mitochondrial.
Conclusions: Our findings demonstrate that melatonin plays a role in regulating mitochondrial quality control in sepsis-induced hepatocytes. It achieves this result by promoting mitophagy and inducing mitochondrial biogenesis, thereby selectively eliminating dysfunctional mitochondria.
Sci Adv. 2023 Jul 21. 9(29): eadh3347

Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.

Wesley Peng, Leonie F Schröder, Pingping Song, Yvette C Wong, Dimitri Krainc.

Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

DOI: https://doi.org/10.1126/sciadv.adh3347
PLoS Pathog. 2023 Jul 17. 19(7): e1011548

The mitophagy receptor NIX induces vIRF-1 oligomerization and interaction with GABARAPL1 for the promotion of HHV-8 reactivation-induced mitophagy.

Mai Tram Vo, Chang-Yong Choi, Young Bong Choi.

Recently, viruses have been shown to regulate selective autophagy for productive infections. For instance, human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), activates selective autophagy of mitochondria, termed mitophagy, thereby inhibiting antiviral innate immune responses during lytic infection in host cells. We previously demonstrated that HHV-8 viral interferon regulatory factor 1 (vIRF-1) plays a crucial role in lytic replication-activated mitophagy by interacting with cellular mitophagic proteins, including NIX and TUFM. However, the precise molecular mechanisms by which these interactions lead to mitophagy activation remain to be determined. Here, we show that vIRF-1 binds directly to mammalian autophagy-related gene 8 (ATG8) proteins, preferentially GABARAPL1 in infected cells, in an LC3-interacting region (LIR)-independent manner. Accordingly, we identified key residues in vIRF-1 and GABARAPL1 required for mutual interaction and demonstrated that the interaction is essential for mitophagy activation and HHV-8 productive replication. Interestingly, the mitophagy receptor NIX promotes vIRF-1-GABARAPL1 interaction, and NIX/vIRF-1-induced mitophagy is significantly inhibited in GABARAPL1-deficient cells. Moreover, a vIRF-1 variant defective in GABARAPL1 binding substantially loses the ability to induce vIRF-1/NIX-induced mitophagy. These results suggest that NIX supports vIRF-1 activity as a mitophagy mediator. In addition, we found that NIX promotes vIRF-1 aggregation and stabilizes aggregated vIRF-1. Together, these findings indicate that vIRF-1 plays a role as a viral mitophagy mediator that can be activated by a cellular mitophagy receptor.

DOI: https://doi.org/10.1371/journal.ppat.1011548
Cell Mol Life Sci. 2023 Jul 18. 80(8): 213

DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction.

Hang Zhu, Jin Wang, Ting Xin, Shanshan Chen, Ruiying Hu, Yukun Li, Mingming Zhang, Hao Zhou.

  Dual specificity phosphatase 1 (DUSP1) and valosin-containing protein (VCP) have both been reported to regulate mitochondrial homeostasis. However, their impact on mitochondrial quality control (MQC) and myocardial function during LPS-induced endotoxemia remains unclear. We addressed this issue by modeling LPS-induced endotoxemia in DUSP1 transgenic (DUSP1TG) mice and in cultured DUSP1-overexpressing HL-1 cardiomyocytes. Accompanying characteristic structural and functional deficits, cardiac DUSP1 expression was significantly downregulated following endotoxemia induction in wild type mice. In contrast, markedly reduced myocardial inflammation, cardiomyocyte apoptosis, cardiac structural disorder, cardiac injury marker levels, and normalized systolic/diastolic function were observed in DUSP1TG mice. Furthermore, DUSP1 overexpression in HL-1 cells significantly attenuated LPS-mediated mitochondrial dysfunction by preserving MQC, as indicated by normalized mitochondrial dynamics, improved mitophagy, enhanced biogenesis, and attenuated mitochondrial unfolded protein response. Molecular assays showed that VCP was a substrate of DUSP1 and the interaction between DUSP1 and VCP primarily occurred on the mitochondria. Mechanistically, DUSP1 phosphatase domain promoted the physiological DUSP1/VCP interaction which prevented LPS-mediated VCP Ser784 phosphorylation. Accordingly, transfection with a phosphomimetic VCP mutant abolished the protective actions of DUSP1 on MQC and aggravated inflammation, apoptosis, and contractility/relaxation capacity in HL-1 cardiomyocytes. These findings support the involvement of the novel DUSP1/VCP/MQC pathway in the pathogenesis of endotoxemia-caused myocardial dysfunction.

Keywords:  Apoptosis; DUSP1; Endotoxemia-caused myocardial dysfunction; Mitochondria; Mitochondrial quality control; Myocardial inflammation; Oxidative stress; VCP

DOI:  https://doi.org/10.1007/s00018-023-04863-z
Mitochondrion. 2023 Jul 13. pii: S1567-7249(23)00057-0. [Epub ahead of print]72 11-21

Type 1 diabetes mellitus: Inflammation, mitophagy, and mitochondrial function.

Alexander V Blagov, Volha I Summerhill, Vasily N Sukhorukov, Mikhail A Popov, Andrey V Grechko, Alexander N Orekhov.

  Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease characterized by the damage of insulin-secreting β-cells in the pancreatic islets of Langerhans. To date, its etiology is not fully understood, despite decades of active search for root causes, and that underlines the complexity of the disease pathogenesis. It was found that mitophagy plays a regulatory role in the development of autoimmune response during T1DM pathogenesis by preventing the accumulation of defective/dysfunctional mitochondria in pancreatic cells. Mitochondrial dysfunction due to impaired mitophagy with the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) contributes to initiating an inflammatory response by elevating pro-inflammatory cytokines and interacting with receptors like those involved in the pathogen-associated response. Moreover, mtROS and mtDNA activate pathways leading to the development of chronic inflammation, which is tightly implicated in T1DM autoimmunity. In this review, we summarized the evidence highlighting the functional role of mitophagy and mitochondria in the development of immune response and chronic inflammation during T1DM pathogenesis. Several anti-inflammatory and mitophagy-related treatment options have been explored.

Keywords:  Chronic inflammation; Inflammation; Mitochondria; Mitochondrial DNA; Mitochondrial ROS; Mitophagy; Type 1 diabetes mellitus

DOI:  https://doi.org/10.1016/j.mito.2023.07.002
Cell Death Dis. 2023 Jul 19. 14(7): 448

Hypoxia-induced mitochondrial stress granules.

Chun-Ling Sun, Marc Van Gilst, C Michael Crowder.

Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.

DOI: https://doi.org/10.1038/s41419-023-05988-6