bims-minimp 2021-08-29 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021–08–29
twenty-two papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

The Unusual Immune System of the Naked Mole-Rat.
Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections.
Substrates and interactors of the ClpP protease in the mitochondria.
Quality control of protein import into mitochondria.
Interactions of Mitochondrial Transcription Factor A with DNA Damage: Mechanistic Insights and Functional Implications.
Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer's Disease.
Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within.
NAD(H) Regulates the Permeability Transition Pore in Mitochondria through an External Site.
Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation.
Fatal attraction - The role of hypoxia when alpha-synuclein gets intimate with mitochondria.
Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation.
The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.
Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia.
A conventional immune regulator MAVS blocks hepatic steatosis via maintaining mitochondrial homeostasis.
Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.
Identification of a quality-control factor that monitors failures during proteasome assembly.
The chaperone HSPB1 prepares protein aggregates for resolubilization by HSP70.
Mitochondria control pyroptosis.
Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes.
Rcf proteins and their differential specificity for respiratory chain complexes: A unique role for Rcf2 on oxygen sensitive supercomplexes?
Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions.
The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets.

Adv Exp Med Biol. 2021 ;1319 315-327

The Unusual Immune System of the Naked Mole-Rat.

Tzuhua Lin, Rochelle Buffenstein.

  The immune system plays a critical role in host defense to pathogens, tissue homeostasis, cancer development, and several aging-associated chronic inflammatory diseases. The naked mole-rat (Heterocephalus glaber) is a subterranean rodent with both extraordinary longevity and cancer-resistant phenotypes. Unlike the immune system of standard laboratory rodents, that of the naked mole-rat features a higher myeloid-to-lymphoid ratio, lacks natural killer cells, has higher pro-inflammatory cytokine production in macrophages, and exhibits a novel LPS-responsive neutrophil subset that highly expresses several antimicrobials. Given these unusual features, the potential involvement of the naked mole-rat's immune system in their longevity and cancer-resistance remains enigmatic. In this chapter, we summarize the current knowledge of the immune system in the naked mole-rat, including the immune cell repertoire, the primary and secondary lymphoid organs, and the inflammatory responses to the pathogenic stimulation such as bacterial toxins. We compare these findings to published studies of the other subterranean rodents and discuss how the environmental factors in which they have evolved may have influenced their immune function.

Keywords:  Immune system; Inflammation; Longevity; Naked mole-rat; Natural killer cell

DOI:  https://doi.org/10.1007/978-3-030-65943-1_12
Cell Rep. 2021 Aug 24. pii: S2211-1247(21)01052-4. [Epub ahead of print]36(8): 109614

Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections.

Zsofi Digby, Panagiotis Tourlomousis, James Rooney, Joseph P Boyle, Betsaida Bibo-Verdugo, Robert J Pickering, Steven J Webster, Thomas P Monie, Lee J Hopkins, Nobuhiko Kayagaki, Guy S Salvesen, Soren Warming, Lucy Weinert, Clare E Bryant.

  Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1β. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.

Keywords:  Carnivora; NLRC4; NLRP3; caspase 1; caspase 11; caspase 4; inflammasome

DOI:  https://doi.org/10.1016/j.celrep.2021.109614
Curr Opin Chem Biol. 2021 Aug 23. pii: S1367-5931(21)00100-9. [Epub ahead of print]

Substrates and interactors of the ClpP protease in the mitochondria.

Mark F Mabanglo, Vaibhav Bhandari, Walid A Houry.

  The ClpP protease is found across eukaryotic and prokaryotic organisms. It is well-characterized in bacteria where its function is important in maintaining protein homeostasis. Along with its ATPase partners, it has been shown to play critical roles in the regulation of enzymes involved in important cellular pathways. In eukaryotes, ClpP is found within cellular organelles. Proteomic studies have begun to characterize the role of this protease in the mitochondria through its interactions. Here, we discuss the proteomic techniques used to identify its interactors and present an atlas of mitochondrial ClpP substrates. The ClpP substrate pool is extensive and consists of proteins involved in essential mitochondrial processes such as the Krebs cycle, oxidative phosphorylation, translation, fatty acid metabolism, and amino acid metabolism. Discoveries of these associations have begun to illustrate the functional significance of ClpP in human health and disease.

Keywords:  Cancer; ClpP protease; Mitochondria; Mitochondrial diseases; Parkinson's disease; Protein quality control; Proteolysis; Proteomics; Proteostasis

DOI:  https://doi.org/10.1016/j.cbpa.2021.07.003
Biochem J. 2021 Aug 27. 478(16): 3125-3143

Quality control of protein import into mitochondria.

Fabian den Brave, Jeannine Engelke, Thomas Becker.

  Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.

Keywords:  TIM23 complex; TOM complex; mitochondria; protein sorting; protein transport

DOI:  https://doi.org/10.1042/BCJ20190584
Genes (Basel). 2021 Aug 15. pii: 1246. [Epub ahead of print]12(8):

Interactions of Mitochondrial Transcription Factor A with DNA Damage: Mechanistic Insights and Functional Implications.

Krystie Chew, Linlin Zhao.

  Mitochondria have a plethora of functions in eukaryotic cells, including cell signaling, programmed cell death, protein cofactor synthesis, and various aspects of metabolism. The organelles carry their own genomic DNA, which encodes transfer and ribosomal RNAs and crucial protein subunits in the oxidative phosphorylation system. Mitochondria are vital for cellular and organismal functions, and alterations of mitochondrial DNA (mtDNA) have been linked to mitochondrial disorders and common human diseases. As such, how the cell maintains the integrity of the mitochondrial genome is an important area of study. Interactions of mitochondrial proteins with mtDNA damage are critically important for repairing, regulating, and signaling mtDNA damage. Mitochondrial transcription factor A (TFAM) is a key player in mtDNA transcription, packaging, and maintenance. Due to the extensive contact of TFAM with mtDNA, it is likely to encounter many types of mtDNA damage and secondary structures. This review summarizes recent research on the interaction of human TFAM with different forms of non-canonical DNA structures and discusses the implications on mtDNA repair and packaging.

Keywords:  DNA modification; DNA packing; DNA-protein interaction; G-quadruplex; epigenetics; nucleoid; post-translational modification

DOI:  https://doi.org/10.3390/genes12081246
Biomedicines. 2021 Jul 24. pii: 881. [Epub ahead of print]9(8):

Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer's Disease.

Tânia Fernandes, Rosa Resende, Diana F Silva, Ana P Marques, Armanda E Santos, Sandra M Cardoso, M Rosário Domingues, Paula I Moreira, Cláudia F Pereira.

  Alzheimer's disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-β (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau. AD-related neurodegenerative mechanisms involve early changes of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and impairment of cellular events modulated by these subcellular domains. In this study, we characterized the structural and functional alterations at MAM, mitochondria, and ER/microsomes in a mouse neuroblastoma cell line (N2A) overexpressing the human amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). Proteins levels were determined by Western blot, ER-mitochondria contacts were quantified by transmission electron microscopy, and Ca2+ homeostasis and mitochondria function were analyzed using fluorescent probes and Seahorse assays. In this in vitro AD model, we found APP accumulated in MAM and mitochondria, and altered levels of proteins implicated in ER-mitochondria tethering, Ca2+ signaling, mitochondrial dynamics, biogenesis and protein import, as well as in the stress response. Moreover, we observed a decreased number of close ER-mitochondria contacts, activation of the ER unfolded protein response, reduced Ca2+ transfer from ER to mitochondria, and impaired mitochondrial function. Together, these results demonstrate that several subcellular alterations occur in AD-like neuronal cells, which supports that the defective ER-mitochondria crosstalk is an important player in AD physiopathology.

Keywords:  Alzheimer’s disease; Ca2+ signaling; ER-mitochondria contacts; mitochondrial dysfunction; subcellular fractions

DOI:  https://doi.org/10.3390/biomedicines9080881
Int J Mol Sci. 2021 Aug 07. pii: 8523. [Epub ahead of print]22(16):

Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within.

Marta Luna-Sánchez, Patrizia Bianchi, Albert Quintana.

  Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.

Keywords:  antiviral response; inflammation; innate immunity; interferon; mitochondrial disorders; mitochondrial dysfunction; mtDNA; mtRNA; neurodegeneration

DOI:  https://doi.org/10.3390/ijms22168523
Int J Mol Sci. 2021 Aug 09. pii: 8560. [Epub ahead of print]22(16):

NAD(H) Regulates the Permeability Transition Pore in Mitochondria through an External Site.

Ekaterina Kharechkina, Anna Nikiforova, Alexey Kruglov.

  The opening of the permeability transition pore (mPTP) in mitochondria initiates cell death in numerous diseases. The regulation of mPTP by NAD(H) in the mitochondrial matrix is well established; however, the role of extramitochondrial (cytosolic) NAD(H) is still unclear. We studied the effect of added NADH and NAD+ on: (1) the Ca2+-retention capacity (CRC) of isolated rat liver, heart, and brain mitochondria; (2) the Ca2+-dependent mitochondrial swelling in media whose particles can (KCl) or cannot (sucrose) be extruded from the matrix by mitochondrial carriers; (3) the Ca2+-dependent mitochondrial depolarization and the release of entrapped calcein from mitochondria of permeabilized hepatocytes; and (4) the Ca2+-dependent mitochondrial depolarization and subsequent repolarization. NADH and NAD+ increased the CRC of liver, heart, and brain mitochondria 1.5-2.5 times, insignificantly affecting the rate of Ca2+-uptake and the free Ca2+ concentration in the medium. NAD(H) suppressed the Ca2+-dependent mitochondrial swelling both in KCl- and sucrose-based media but did not induce the contraction and repolarization of swollen mitochondria. By contrast, EGTA caused mitochondrial repolarization in both media and the contraction in KCl-based medium only. NAD(H) delayed the Ca2+-dependent depolarization and the release of calcein from individual mitochondria in hepatocytes. These data unambiguously demonstrate the existence of an external NAD(H)-dependent site of mPTP regulation.

Keywords:  NAD+; NADH; calcium retention capacity; cytosolic; external regulatory site; permeability transition pore; pore closure

DOI:  https://doi.org/10.3390/ijms22168560
Cell Chem Biol. 2021 Aug 24. pii: S2451-9456(21)00365-2. [Epub ahead of print]

Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation.

Takuya Hidaka, Kaori Hashiya, Toshikazu Bando, Ganesh N Pandian, Hiroshi Sugiyama.

  Mutations in mitochondrial DNA (mtDNA) cause mitochondrial diseases, characterized by abnormal mitochondrial function. Although eliminating mutated mtDNA has potential to cure mitochondrial diseases, no chemical-based drugs in clinical trials are capable of selective modulation of mtDNA mutations. Here, we construct a class of compounds encompassing pyrrole-imidazole polyamides (PIPs), mitochondria-penetrating peptide, and chlorambucil, an adenine-specific DNA-alkylating reagent. The sequence-selective DNA binding of PIPs allows chlorambucil to alkylate mutant adenine more efficiently than other sites in mtDNA. In vitro DNA alkylation assay shows that our compound 8950A-Chb(Cl/OH) targeting a nonpathogenic point mutation in HeLa S3 cells (m.8950G>A) can specifically alkylate the mutant adenine. Furthermore, the compound reduces the mtDNA possessing the target mutation in cultured HeLa S3 cells. The programmability of PIPs to target different sequences could allow this class of compounds to be developed as designer drugs targeting pathogenic mutations associated with mitochondrial diseases in future studies.

Keywords:  DNA alkylation; DNA mutation; designer small molecule; heteroplasmy; mitochondria; mitochondrial DNA; mitochondrial disease; pyrrole-imidazole polyamide

DOI:  https://doi.org/10.1016/j.chembiol.2021.08.003
Neurobiol Aging. 2021 Jul 31. pii: S0197-4580(21)00243-8. [Epub ahead of print]107 128-141

Fatal attraction - The role of hypoxia when alpha-synuclein gets intimate with mitochondria.

Johannes Burtscher, Muhammed Muazzam Kamil Syed, Markus A Keller, Hilal A Lashuel, Grégoire P Millet.

  Alpha-synuclein aggregation and mitochondrial dysfunction are main pathological hallmarks of Parkinson's disease (PD) and several other neurodegenerative diseases, collectively known as synucleinopathies. However, increasing evidence suggests that they may not be sufficient to cause PD. Here we propose the role of hypoxia as a missing link that connects the complex interplay between alpha-synuclein biochemistry and pathology, mitochondrial dysfunctions and neurodegeneration in PD. We review the partly conflicting literature on alpha-synuclein binding to membranes and mitochondria and its impact on mitochondrial functions. From there, we focus on adverse changes in cellular environments, revolving around hypoxic stress, that may trigger or facilitate PD progression. Inter-dependent structural re-arrangements of mitochondrial membranes, including increased cytoplasmic exposure of mitochondrial cardiolipins and changes in alpha-synuclein localization and conformation are discussed consequences of such conditions. Enhancing cellular resilience could be an integral part of future combination-based therapies of PD. This may be achieved by boosting the capacity of cellular and specifically mitochondrial processes to regulate and adapt to altered proteostasis, redox, and inflammatory conditions and by inducing protective molecular and tissue re-modelling.

Keywords:  Alpha-synuclein; Cardiolipin; Conditioning; Hypoxia; Mitochondria; Neurodegeneration

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.07.017
Cell Rep. 2021 Aug 24. pii: S2211-1247(21)00999-2. [Epub ahead of print]36(8): 109565

Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation.

Miriam Valera-Alberni, Magali Joffraud, Joan Miro-Blanch, Jordi Capellades, Alexandra Junza, Loïc Dayon, Antonio Núñez Galindo, Jose L Sanchez-Garcia, Armand Valsesia, Angelique Cercillieux, Flavia Söllner, Andreas G Ladurner, Oscar Yanes, Carles Cantó.

  Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood. Here, we describe the functional interrelation between S579 and S600 phosphorylation sites in vivo and their role on mitochondrial remodeling. Mice carrying a homozygous Drp1 S600A knockin (Drp1 KI) mutation display larger mitochondria and enhanced lipid oxidation and respiratory capacities, granting improved glucose tolerance and thermogenic response upon high-fat feeding. Housing mice at thermoneutrality blunts these differences, suggesting a role for the brown adipose tissue in the protection of Drp1 KI mice against metabolic damage. Overall, we demonstrate crosstalk between Drp1 phosphorylation sites and provide evidence that their modulation could be used in the treatment and prevention of metabolic diseases.

Keywords:  Drp1; brown adipose tissue; insulin resistance; metabolic syndrome; mitochondrial dynamics; mitochondrial respiration; phosphorylation; thermoneutrality

DOI:  https://doi.org/10.1016/j.celrep.2021.109565
FEBS J. 2021 Aug 24.

The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.

Rishi Banerjee, Janne Purhonen, Jukka Kallijärvi.

  Coenzyme Q (CoQ, ubiquinone) is the electron-carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH-dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron-transferring flavoprotein dehydrogenase, mitochondrial glycerol-3-phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ-linked metabolism depends on CoQ re-oxidation by the mitochondrial complex III (cytochrome bc1 complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ-linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ-dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.

Keywords:  coenzyme Q; complex III; mitochondrial disease; oxidative phosphorylation; ubiquinone

DOI:  https://doi.org/10.1111/febs.16164
Int J Mol Sci. 2021 Aug 11. pii: 8636. [Epub ahead of print]22(16):

Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia.

Ludmila Lukyanova, Elita Germanova, Natalya Khmil, Lybov Pavlik, Irina Mikheeva, Maria Shigaeva, Galina Mironova.

  This study was the first comprehensive investigation of the dependence of mitochondrial enzyme response (catalytic subunits of mitochondrial complexes (MC) I-V, including NDUFV2, SDHA, Cyt b, COX1 and ATP5A) and mitochondrial ultrastructure in the rat cerebral cortex (CC) on the severity and duration of in vivo hypoxic exposures. The role of individual animal's resistance to hypoxia was also studied. The respiratory chain (RC) was shown to respond to changes in environmental [O2] as follows: (a) differential reaction of mitochondrial enzymes, which depends on the severity of the hypoxic exposure and which indicates changes in the content and catalytic properties of mitochondrial enzymes, both during acute and multiple exposures; and (b) ultrastructural changes in mitochondria, which reflect various degrees of mitochondrial energization. Within a specific range of reduced O2 concentrations, activation of the MC II is a compensatory response supporting the RC electron transport function. In this process, MC I develops new kinetic properties, and its function recovers in hypoxia by reprograming the RC substrate site. Therefore, the mitochondrial RC performs as an in vivo molecular oxygen sensor. Substantial differences between responses of rats with high and low resistance to hypoxia were determined.

Keywords:  adaptation to hypoxia; catalytic subunits of mitochondrial complexes (MC- I-V); mitochondrial dynamics; mitochondrial enzymes

DOI:  https://doi.org/10.3390/ijms22168636
Hepatology. 2021 Aug 26.

A conventional immune regulator MAVS blocks hepatic steatosis via maintaining mitochondrial homeostasis.

Jiajun Fu, Fengjiao Hu, Tengfei Ma, Wen-Jie Zhao, Han Tian, Yan Zhang, Manli Hu, Junjie Zhou, Yanfang Zhang, Chongshu Jian, Yan-Xiao Ji, Xiao-Jing Zhang, Jingwei Jiang, Zhi-Gang She, Xu Cheng, Peng Zhang, Lan Bai, Juan Yang, Hongliang Li.

   BACKGROUND & AIMS: Although the prevalence of nonalcoholic fatty liver disease (NAFLD) has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease due to uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown.
APPROACH & RESULTS: Based on expression analysis, we identified a marked downregulation of MAVS in hepatocytes during NAFLD progression. By employing MAVS global knockout and hepatocyte-specific MAVS knockout mice, we found that MAVS is protective against diet-induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N-terminal stretch of voltage-dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis.
CONCLUSIONS: In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide new insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent a new avenue for treating NAFLD.

Keywords:  MAVS; NAFLD; VDAC2; lipid metabolism; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/hep.32126
Nat Med. 2021 Aug 23.

Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

ICICLE-PD Study Group

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.

DOI: https://doi.org/10.1038/s41591-021-01441-3
Science. 2021 Aug 27. 373(6558): 998-1004

Identification of a quality-control factor that monitors failures during proteasome assembly.

Eszter Zavodszky, Sew-Yeu Peak-Chew, Szymon Juszkiewicz, Ana J Narvaez, Ramanujan S Hegde.

In eukaryotic cells, half of all proteins function as subunits within multiprotein complexes. Imbalanced synthesis of subunits leads to unassembled intermediates that must be degraded to minimize cellular toxicity. Here, we found that excess PSMC5, a subunit of the proteasome base, was targeted for degradation by the HERC1 ubiquitin ligase in mammalian cells. HERC1 identified unassembled PSMC5 by its cognate assembly chaperone PAAF1. Because PAAF1 only dissociates after assembly, HERC1 could also engage later assembly intermediates such as the PSMC4-PSMC5-PAAF1 complex. A missense mutant of HERC1 that causes neurodegeneration in mice was impaired in the recognition and ubiquitination of the PSMC5-PAAF1 complex. Thus, proteasome assembly factors can serve as adaptors for ubiquitin ligases to facilitate elimination of unassembled intermediates and maintain protein homeostasis.

DOI: https://doi.org/10.1126/science.abc6500
Sci Rep. 2021 Aug 24. 11(1): 17139

The chaperone HSPB1 prepares protein aggregates for resolubilization by HSP70.

Conrado C Gonçalves, Itai Sharon, T Martin Schmeing, Carlos H I Ramos, Jason C Young.

In human cells under stress conditions, misfolded polypeptides can form potentially cytotoxic insoluble aggregates. To eliminate aggregates, the HSP70 chaperone machinery extracts and resolubilizes polypeptides for triage to refolding or degradation. Yeast and bacterial chaperones of the small heat-shock protein (sHSP) family can bind substrates at early stages of misfolding, during the aggregation process. The co-aggregated sHSPs then facilitate downstream disaggregation by HSP70. Because it is unknown whether a human sHSP has this activity, we investigated the disaggregation role of human HSPB1. HSPB1 co-aggregated with unfolded protein substrates, firefly luciferase and mammalian lactate dehydrogenase. The co-aggregates formed with HSPB1 were smaller and more regularly shaped than those formed in its absence. Importantly, co-aggregation promoted the efficient disaggregation and refolding of the substrates, led by HSP70. HSPB1 itself was also extracted during disaggregation, and its homo-oligomerization ability was not required. Therefore, we propose that a human sHSP is an integral part of the chaperone network for protein disaggregation.

DOI: https://doi.org/10.1038/s41598-021-96518-x
Nat Immunol. 2021 09;22(9): 1071

Mitochondria control pyroptosis.

Nicholas J Bernard.

DOI: https://doi.org/10.1038/s41590-021-01017-w
Cell Metab. 2021 Aug 17. pii: S1550-4131(21)00365-X. [Epub ahead of print]

Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes.

Clair Crewe, Jan-Bernd Funcke, Shujuan Li, Nolwenn Joffin, Christy M Gliniak, Alexandra L Ghaben, Yu A An, Hesham A Sadek, Ruth Gordillo, Yucel Akgul, Shiuhwei Chen, Dmitri Samovski, Pamela Fischer-Posovszky, Christine M Kusminski, Samuel Klein, Philipp E Scherer.

  Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.

Keywords:  adipocyte; cardiovascular disease; diabetes; exosomes; extracellular vesicles; mitochondria; mitochondrial dysfunction; mitohormesis; obesity; stress response

DOI:  https://doi.org/10.1016/j.cmet.2021.08.002
Biochim Biophys Acta Mol Cell Res. 2021 Aug 24. pii: S0167-4889(21)00187-7. [Epub ahead of print] 119133

Rcf proteins and their differential specificity for respiratory chain complexes: A unique role for Rcf2 on oxygen sensitive supercomplexes?

Bettina Homberg, Katharina Römpler, Mirjam Wissel, Sylvie Callegari, Markus Deckers.

  The respiratory chain, embedded in the inner mitochondrial membrane, is organized as a network of individual complexes, as well as large supercomplex structures. In the yeast S. cerevisiae, these supercomplexes consist of a dimeric cytochrome bc1-complex adjoined by one or two copies of cytochrome c oxidase. The formation of these complexes is a dynamic process and is regulated by various factors in order to adapt to environmental and metabolic changes. These adaptions occur at the level of enzyme regulation, complex assembly, as well as altered nuclear and mitochondrial transcription and translation. Members of the Rcf protein family (Rcf1, Rcf2 and Rcf3) are required for respiratory complex biogenesis and act mainly by regulating the assembly and enzyme activity of complex IV within supercomplexes. Rcf1 functions in the assembly process via the COX3 module, whereas Rcf2 and Rcf3 are responsible for enzymatic regulation. In this study, we have extended this knowledge to show that Rcf2 and Rcf3 can also associate with newly synthesized proteins, such as Cox3, and therefore contribute to complex IV assembly. Since the Rcf proteins have overlapping regions of sequence similarities, we engineered novel fusion proteins of Rcf1 and Rcf3, with parts of Rcf2, to probe which of the Rcf protein domains can be attributed to their functions. The fusion proteins could compensate for the individual phenotypes of the complex IV assembly defect and the lack of complex IV regulation. Finally, the role of Rcf proteins for defined species of respiratory chain complexes in a hypoxic model was investigated, uncovering a unique association of Rcf2 with the hypoxic III2IV supercomplex. We therefore suggest an involvement of Rcf2 for adaption of the respiratory chain to altering oxygen levels.

Keywords:  OXPHOS; mitochondria; respiratory chain supercomplexes

DOI:  https://doi.org/10.1016/j.bbamcr.2021.119133
J Mol Med (Berl). 2021 Aug 25.

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions.

Antero Salminen.

  The functional competence of the immune system gradually declines with aging, a process called immunosenescence. The age-related remodelling of the immune system affects both adaptive and innate immunity. In particular, a chronic low-grade inflammation, termed inflammaging, is associated with the aging process. Immunosenescence not only is present in inflammaging state, but it also occurs in several pathological conditions in conjunction with chronic inflammation. It is known that persistent inflammation stimulates a counteracting compensatory immunosuppression intended to protect host tissues. Inflammatory mediators enhance myelopoiesis and induce the generation of immature myeloid-derived suppressor cells (MDSC) which in mutual cooperation stimulates the immunosuppressive network. Immunosuppressive cells, especially MDSCs, regulatory T cells (Treg), and M2 macrophages produce immunosuppressive factors, e.g., TGF-β, IL-10, ROS, arginase-1 (ARG1), and indoleamine 2,3-dioxygenase (IDO), which suppress the functions of CD4/CD8T and B cells as well as macrophages, natural killer (NK) cells, and dendritic cells. The immunosuppressive armament (i) inhibits the development and proliferation of immune cells, (ii) decreases the cytotoxic activity of CD8T and NK cells, (iii) prevents antigen presentation and antibody production, and (iv) suppresses responsiveness to inflammatory mediators. These phenotypes are the hallmarks of immunosenescence. Immunosuppressive factors are able to control the chromatin landscape, and thus, it seems that the immunosenescence state is epigenetically regulated.

Keywords:  Aging; Alzheimer’s; Cellular senescence; Immune tolerance; Immunosuppression; Kynurenine

DOI:  https://doi.org/10.1007/s00109-021-02123-w
Int J Mol Sci. 2021 Aug 16. pii: 8770. [Epub ahead of print]22(16):

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets.

Siarhei A Dabravolski, Nikita G Nikiforov, Antonina V Starodubova, Tatyana V Popkova, Alexander N Orekhov.

  Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.

Keywords:  Humanin; MOTS-c; SHLPs; ageing; atherosclerosis; cardiovascular diseases; hyperlipidaemia; insulin resistance; mitochondria-derived peptides

DOI:  https://doi.org/10.3390/ijms22168770