bims-minimp 2022-01-16 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒01‒16
thirteen papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Mitochondria shed their outer membrane in response to infection-induced stress.
Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
DRP1 interacts directly with BAX to induce its activation and apoptosis.
NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.
Dynamic Distribution of HIG2A between the Mitochondria and the Nucleus in Response to Hypoxia and Oxidative Stress.
Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.
Structural basis of BAK activation in mitochondrial apoptosis initiation.
Mitochondrial repair as potential pharmacological target in cerebral ischemia.
The RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation.
Mitochondrial complex-I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.
PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis.
Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice.

Science. 2022 Jan 14. 375(6577): eabi4343

Mitochondria shed their outer membrane in response to infection-induced stress.

Xianhe Li, Julian Straub, Tânia Catarina Medeiros, Chahat Mehra, Fabian den Brave, Esra Peker, Ilian Atanassov, Katharina Stillger, Jonas Benjamin Michaelis, Emma Burbridge, Colin Adrain, Christian Münch, Jan Riemer, Thomas Becker, Lena F Pernas.

[Figure: see text].

DOI: https://doi.org/10.1126/science.abi4343
Int J Mol Sci. 2021 Dec 21. pii: 7. [Epub ahead of print]23(1):

Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.

Anna M Lenkiewicz, Magda Krakowczyk, Piotr Bragoszewski.

  With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

Keywords:  mitochondrial biogenesis; molecular chaperone; proteasome; protein degradation; protein precursor; protein transport; proteostasis; quality control; ubiquitin

DOI:  https://doi.org/10.3390/ijms23010007
Cell Metab. 2022 Jan 07. pii: S1550-4131(21)00636-7. [Epub ahead of print]

Mosaic dysfunction of mitophagy in mitochondrial muscle disease.

Takayuki Mito, Amy E Vincent, Julie Faitg, Robert W Taylor, Nahid A Khan, Thomas G McWilliams, Anu Suomalainen.

  Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.

Keywords:  SBFSEM; centrally nucleated fibers; lysosome; mito-QC; mitochondrial disease; mitochondrial myopathy; mitophagy; patient; ragged-red fibers

DOI:  https://doi.org/10.1016/j.cmet.2021.12.017
EMBO J. 2022 Jan 13. e108587

DRP1 interacts directly with BAX to induce its activation and apoptosis.

Andreas Jenner, Aida Peña-Blanco, Raquel Salvador-Gallego, Begoña Ugarte-Uribe, Cristiana Zollo, Tariq Ganief, Jan Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer, Boris Macek, Ana J Garcia-Saez.

  The apoptotic executioner protein BAX and the dynamin-like protein DRP1 co-localize at mitochondria during apoptosis to mediate mitochondrial permeabilization and fragmentation. However, the molecular basis and functional consequences of this interplay remain unknown. Here, we show that BAX and DRP1 physically interact, and that this interaction is enhanced during apoptosis. Complex formation between BAX and DRP1 occurs exclusively in the membrane environment and requires the BAX N-terminal region, but also involves several other BAX surfaces. Furthermore, the association between BAX and DRP1 enhances the membrane activity of both proteins. Forced dimerization of BAX and DRP1 triggers their activation and translocation to mitochondria, where they induce mitochondrial remodeling and permeabilization to cause apoptosis even in the absence of apoptotic triggers. Based on this, we propose that DRP1 can promote apoptosis by acting as noncanonical direct activator of BAX through physical contacts with its N-terminal region.

Keywords:  BCL-2 proteins; fluorescence correlation spectroscopy; membrane protein complex; mitochondrial division; super-resolution microscopy

DOI:  https://doi.org/10.15252/embj.2021108587
Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01710-1. [Epub ahead of print]38(2): 110206

NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.

Rendan Yang, Yamei Li, Yanli Wang, Jingjing Zhang, Qijing Fan, Jianlin Tan, Weizhen Li, Xiaoju Zou, Bin Liang.

  Mitochondria are known as the powerhouse of the cell. Dysfunction of mitochondria homeostasis induces the mitochondrial unfolded protein response (UPRmt), altering cellular metabolism. How cells sense the UPRmt to rewire metabolism is largely unknown. Here, we show that inactivation of either the citric/tricarboxylic acid (TCA) cycle enzymes aco-2 or idha-1, which encode aconitase and isocitrate dehydrogenase respectively, leads to citrate accumulation. In Caenorhabditis elegans, both in vitro and in vivo, citrate accumulation consequently triggers the UPRmt and also promotes lipid accumulation. The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression. NHR-80 then upregulates lipogenesis and lipid accumulation, shifting excess citrate for use in lipogenesis and for storage as triacylglycerol in lipid droplets. Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation. Therefore, our work uncovers a DVE-1-NHR-80-lipogenesis axis linking the transmission of the mitochondrial stress signal to lipid metabolism.

Keywords:  citrate; citric/tricarboxylic acid (TCA) cycle; lipid accumulation; mitochondrial unfolded protein response (UPR(mt)); nuclear hormone receptor NHR-80

DOI:  https://doi.org/10.1016/j.celrep.2021.110206
Int J Mol Sci. 2021 Dec 30. pii: 389. [Epub ahead of print]23(1):

Dynamic Distribution of HIG2A between the Mitochondria and the Nucleus in Response to Hypoxia and Oxidative Stress.

Celia Salazar, Miriam Barros, Alvaro A Elorza, Lina María Ruiz.

  Mitochondrial respiratory supercomplex formation requires HIG2A protein, which also has been associated with cell proliferation and cell survival under hypoxia. HIG2A protein localizes in mitochondria and nucleus. DNA methylation and mRNA expression of the HIGD2A gene show significant alterations in several cancers, suggesting a role for HIG2A in cancer biology. The present work aims to understand the dynamics of the HIG2A subcellular localization under cellular stress. We found that HIG2A protein levels increase under oxidative stress. H2O2 shifts HIG2A localization to the mitochondria, while rotenone shifts it to the nucleus. HIG2A protein colocalized at a higher level in the nucleus concerning the mitochondrial network under normoxia and hypoxia (2% O2). Hypoxia (2% O2) significantly increases HIG2A nuclear colocalization in C2C12 cells. In HEK293 cells, chemical hypoxia with CoCl2 (>1% O2) and FCCP mitochondrial uncoupling, the HIG2A protein decreased its nuclear localization and shifted to the mitochondria. This suggests that the HIG2A distribution pattern between the mitochondria and the nucleus depends on stress and cell type. HIG2A protein expression levels increase under cellular stresses such as hypoxia and oxidative stress. Its dynamic distribution between mitochondria and the nucleus in response to stress factors suggests a new communication system between the mitochondria and the nucleus.

Keywords:  HIGD2A; cancer; hypoxia; metabolic reprograming; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/ijms23010389
Front Mol Biosci. 2021 ;8 769135

Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.

Yifan Ge, Sivakumar Boopathy, Tran H Nguyen, Camila Makhlouta Lugo, Luke H Chao.

  Cardiolipin is a tetra-acylated di-phosphatidylglycerol lipid enriched in the matrix-facing (inner) leaflet of the mitochondrial inner membrane. Cardiolipin plays an important role in regulating mitochondria function and dynamics. Yet, the mechanisms connecting cardiolipin distribution and mitochondrial protein function remain indirect. In our previous work, we established an in vitro system reconstituting mitochondrial inner membrane fusion mediated by Opa1. We found that the long form of Opa1 (l-Opa1) works together with the proteolytically processed short form (s-Opa1) to mediate fast and efficient membrane fusion. Here, we extend our reconstitution system to generate supported lipid bilayers with asymmetric cardiolipin distribution. Using this system, we find the presence of cardiolipin on the inter-membrane space-facing (outer) leaflet is important for membrane tethering and fusion. We discuss how the presence of cardiolipin in this leaflet may influence protein and membrane properties, and future applications for this approach.

Keywords:  OPA1; cardiolipin; membrane asymmetry; membrane heterogeneity; mitochondrial fusion

DOI:  https://doi.org/10.3389/fmolb.2021.769135
Nat Commun. 2022 Jan 11. 13(1): 250

Structural basis of BAK activation in mitochondrial apoptosis initiation.

Geetika Singh, Cristina D Guibao, Jayaraman Seetharaman, Anup Aggarwal, Christy R Grace, Dan E McNamara, Sivaraja Vaithiyalingam, M Brett Waddell, Tudor Moldoveanu.

BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric "BH3-in-groove" triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.

DOI: https://doi.org/10.1038/s41467-021-27851-y
Mitochondrion. 2022 Jan 06. pii: S1567-7249(22)00001-0. [Epub ahead of print]63 23-31

Mitochondrial repair as potential pharmacological target in cerebral ischemia.

Ms Mandeep Kaur, Dr Saurabh Sharma.

  Cerebral ischemia and its consequences like transient ischemic attack, aneurysm and stroke are the common and devastating conditions which remain the leading cause of mortality after coronary heart disease in developed countries and are the greatest cause of disability, leaving 50% of survivors permanently disabled. Despite recognition of risk factors and mechanisms involved in the pathology of the disease, treatment of ischemic disorders is limited to thrombolytic drugs like recombinant tissue plasminogen activator (rt-PA) and clinical rendition of the neuroprotective agents have not been so successful. Recent studies evidenced the role of mitochondrial dysfunction in neuronal damage that occurred after cerebral ischemia. This review article will focus on the various fundamental mechanisms responsible for neuronal damage because of mitochondrial dysfunction including cell signaling pathways, autophagy, apoptosis/necrosis, generation of reactive oxygen species, calcium overload, the opening of membrane permeability transition pore (mPTP), mitochondrial dynamics and biogenesis. Recent studies have concerned the significant role of mitochondrial biogenesis in mitochondrial repair and transfer of healthy mitochondria from astrocytes to the damaged neurons, providing neuroprotection and neural recovery following ischemia. Novel and influential studies have evidenced the significant role of mitochondria transfer and mitochondrial transplantation in reviving cell energy and in replacement of impaired or dysfunctional mitochondria with healthy mitochondria after ischemic episode. This review article will focus on recent advances in mitochondrial interventions and exogenous therapeutic modalities like mitochondria transfer technique, employment of stem cells, mitochondrial transplantation, miRNA inhibition and mitochondrial-targeted Sirtuin1 activator for designing novel and promising treatment for cerebral ischemia induced pathological states.

Keywords:  Cerebral ischemia; Mitochondrial transfer; Mitochondrial transplantation; Mitochondrial dysfunction; Mitophagy; Reactive oxygen species; miRNA inhibition

DOI:  https://doi.org/10.1016/j.mito.2022.01.001
Nat Commun. 2022 Jan 11. 13(1): 209

The RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation.

Nicole Kleiber, Nicolas Lemus-Diaz, Carina Stiller, Marleen Heinrichs, Mandy Mong-Quyen Mai, Philipp Hackert, Ricarda Richter-Dennerlein, Claudia Höbartner, Katherine E Bohnsack, Markus T Bohnsack.

Modified nucleotides in tRNAs are important determinants of folding, structure and function. Here we identify METTL8 as a mitochondrial matrix protein and active RNA methyltransferase responsible for installing m3C32 in the human mitochondrial (mt-)tRNAThr and mt-tRNASer(UCN). METTL8 crosslinks to the anticodon stem loop (ASL) of many mt-tRNAs in cells, raising the question of how methylation target specificity is achieved. Dissection of mt-tRNA recognition elements revealed U34G35 and t6A37/(ms2)i6A37, present concomitantly only in the ASLs of the two substrate mt-tRNAs, as key determinants for METTL8-mediated methylation of C32. Several lines of evidence demonstrate the influence of U34, G35, and the m3C32 and t6A37/(ms2)i6A37 modifications in mt-tRNAThr/Ser(UCN) on the structure of these mt-tRNAs. Although mt-tRNAThr/Ser(UCN) lacking METTL8-mediated m3C32 are efficiently aminoacylated and associate with mitochondrial ribosomes, mitochondrial translation is mildly impaired by lack of METTL8. Together these results define the cellular targets of METTL8 and shed new light on the role of m3C32 within mt-tRNAs.

DOI: https://doi.org/10.1038/s41467-021-27905-1
Eur J Neurol. 2022 Jan 10.

Mitochondrial complex-I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

Tatsuhiro Terada, Joseph Therriault, Min Su Kang, Melissa Savard, Tharick Ali Pascoal, Firoza Lussier, Cecile Tissot, Yi-Ting Wang, Andrea Benedet, Nina Margherita Poltronetti, Julie Ottoy, Jaime Frenandez Arias, Gleb Bezgin, Takashi Matsudaira, Tomoyasu Bunai, Tomokazu Obi, Hideo Tsukada, Yasuomi Ouchi, Pedro Rosa-Neto.

  BACKGROUND: Abnormal mitochondrial metabolism has been described in Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study is to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation, or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET).METHODS: Amyloid and tau positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N=30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18 F]BCPP-EF, [11 C]PiB and [18 F]FDG for assessing brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models.
RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden.
CONCLUSIONS: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, the link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

Keywords:  Alzheimer's disease (AD); [18F]BCPP-EF; mitochondria; positron emission tomography (PET)

DOI:  https://doi.org/10.1111/ene.15246
Cell Death Dis. 2022 01 10. 13(1): 31

PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis.

Bo Young Nam, Jong Hyun Jhee, Jimin Park, Seonghun Kim, Gyuri Kim, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Je-Wook Yu, Seung Hyeok Han.

The NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-β1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-β1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-β1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.

DOI: https://doi.org/10.1038/s41419-021-04480-3
Int J Mol Sci. 2022 Jan 05. pii: 577. [Epub ahead of print]23(1):

Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice.

Ying-Hsien Huang, Feng-Sheng Wang, Pei-Wen Wang, Hung-Yu Lin, Sheng-Dean Luo, Ya-Ling Yang.

  Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria from proteotoxicity under various types of stress. In this study, we investigated whether HSP60 could ameliorate experimental high-fat diet (HFD)-induced obesity and hepatitis and explored the potential mechanism in mice. The results uncovered that HSP60 gain not only alleviated HFD-induced body weight gain, fat accumulation, and hepatocellular steatosis, but also glucose tolerance and insulin resistance according to intraperitoneal glucose tolerance testing and insulin tolerance testing in HSP60 transgenic (HSP60Tg) compared to wild-type (WT) mice by HFD. Furthermore, overexpression of HSP60 in the HFD group resulted in inhibited release of mitochondrial dsRNA (mt-dsRNA) compared to WT mice. In addition, overexpression of HSP60 also inhibited the activation of toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and phosphorylated-interferon regulatory factor 3 (p-IRF3), as well as inflammatory biomarkers such as mRNA of il-1β and il-6 expression in the liver in response to HFD. The in vitro study also confirmed that the addition of HSP-60 mimics in HepG2 cells led to upregulated expression level of HSP60 and restricted release of mt-dsRNA, as well as downregulated expression levels of TLR3, MDA5, and pIRF3. This study provides novel insight into a hepatoprotective effect, whereby HSP60 inhibits the release of dsRNA to repress the TLR3/MDA5/pIRF3 pathway in the context of NAFLD or hepatic inflammation. Therefore, HSP60 may serve as a possible therapeutic target for improving NAFLD.

Keywords:  HSP60; NAFLD; NASH; dsRNA; liver; mitochondria

DOI:  https://doi.org/10.3390/ijms23010577