bims-minimp 2022-03-06 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒03‒06
fourteen papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Long-lived mitochondrial proteins and why they exist.
CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.
Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.
LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.
The case for brakes: Why restrain the size of Bax and Bak pores in outer mitochondrial membranes?
Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.
Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.
MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.
Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains.
Autophagy deficiency abolishes liver mitochondrial DNA segregation.
Metabolomic signature and mitochondrial dynamics outline the difference between vulnerability and resilience to chronic stress.
Bypassing the nuclear gate: A non-canonical entry pathway for the mitochondrial pyruvate dehydrogenase complex.
A common evolutionary origin reveals fundamental principles of protein insertases.

Trends Cell Biol. 2022 Feb 24. pii: S0962-8924(22)00034-4. [Epub ahead of print]

Long-lived mitochondrial proteins and why they exist.

Ewa Bomba-Warczak, Jeffrey N Savas.

  Intracellular long-lived proteins (LLPs) provide structural support for several highly stable protein complexes and assemblies that play essential roles in ensuring cellular homeostasis and function. Recently, mitochondrial long-lived proteins (mt-LLPs) were discovered within inner mitochondria membranes (IMMs) and cristae invagination in tissues with old postmitotic cells. This observation is at odds with the fact that mitochondria are highly dynamic organelles that are continually remodeled through processes of fission, fusion, biogenesis, and multiple quality control pathways. In this opinion article, we propose that a subset of the mitochondrial proteome persists over long time frames and these mt-LLPs provide key structural support for the lifelong maintenance of mitochondrial structure.

Keywords:  cristae ultrastructure; long-lived proteins; mitochondria; mitochondrial dynamics; protein turnover; stable structures

DOI:  https://doi.org/10.1016/j.tcb.2022.02.001
Brain. 2022 Mar 04. pii: awab303. [Epub ahead of print]

CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.

Anastasia Rumyantseva, Milica Popovic, Aleksandra Trifunovic.

  Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. Therefore, it is not surprising that mutations in either mtDNA or nuclear DNA-encoded genes of mitochondrial proteins cause diseases affecting the oxidative phosphorylation system, which are heterogeneous from a clinical, genetic, biochemical and molecular perspective and can affect patients at any age. Despite all this, it is surprising that our understanding of the mechanisms governing mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored. We recently showed that loss of the mitochondrial matrix protease caseinolytic protease proteolytic subunit (CLPP) ameliorates phenotypes in cells characterized by defects in oxidative phosphorylation maintenance. Here, we build upon this finding by showing that CLPP depletion is indeed beneficial in vivo for various types of neuronal populations, including Purkinje cells in the cerebellum and cortical and hippocampal neurons in the forebrain, as it strongly improves distinct phenotypes of mitochondria encephalopathy, driven by the deficiency of the mitochondrial aspartyl tRNA synthase DARS2. In the absence of CLPP, neurodegeneration of DARS2-deficient neurons is delayed as they present milder oxidative phosphorylation dysfunction. This in turn leads to a decreased neuroinflammatory response and significantly improved motor functions in both double-deficient models (Purkinje cell-specific or forebrain neuron-specific Dars2/Clpp double knockout mice). We propose that diminished turnover of respiratory complex I caused by the loss of CLPP is behind the improved phenotype in Dars2/Clpp double knockout animals, even though this intervention might not restore respiratory complex I activity but rather improve mitochondrial cristae morphology or help maintain the NAD+/NADH ratio inside mitochondria. These results also open the possibility of targeting CLPP activity in many other mitochondrial encephalopathies characterized by respiratory complex I instability.

Keywords:  CLPP protease; DARS2 deficiency; LBSL; mitochondrial diseases

DOI:  https://doi.org/10.1093/brain/awab303
Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.

Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.

  Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

Keywords:  S. cerevisiae; cell biology

DOI:  https://doi.org/10.7554/eLife.75658
Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00074-0. [Epub ahead of print]

The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.

Yihang Zhao, Mengzhen Jia, Weixuan Chen, Zhigang Liu.

  Intermittent fasting (IF) has been studied for its effects on lifespan and lifespan as well as the prevention or delay of age-related diseases upon the regulation of metabolic pathways. Mitochondria participate in key metabolic pathways and play important roles in maintaining intracellular signaling networks that modulate various cellular functions. Mitochondrial dysfunction has been described as an early feature of brain aging and neurodegeneration. Although IF has been shown to prevent brain aging and neurodegeneration, the mechanism is still unclear. This review focuses on the mechanisms by which IF improves mitochondrial function, which plays a central role in brain aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The cellular and molecular mechanisms of IF in brain aging and neurodegeneration involve activation of adaptive cellular stress responses and signaling- and transcriptional pathways, thereby enhancing mitochondrial function, by promoting energy metabolism and reducing oxidant production.

Keywords:  Brain aging; Intermittent fasting; Mitochondrial dysfunction; Neurodegeneration

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.021
Development. 2022 Mar 03. pii: dev.200458. [Epub ahead of print]

LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.

Ke Zhao, Xinyi Huang, Wukui Zhao, Bin Lu, Zhongzhou Yang.

  The mitochondrial matrix AAA+ Lon protease (LONP1) degrades misfolded or unassembled proteins, which play a pivotal role in mitochondrial quality control. During heart development, a metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation takes place, and this process relies highly on functional mitochondria. However, the relationship between mitochondrial quality control machinery and metabolic shifts is elusive. Here, we interfered with mitochondrial quality control by inactivating Lonp1 in embryonic cardiac tissue and found severely impaired heart development, leading to embryonic lethality. Mitochondrial swelling, cristae loss and abnormal protein aggregates were evident in the mitochondria of Lonp1-deficient cardiomyocytes. Accordingly, the p-eIF2α-ATF4 pathway was triggered, and nuclear translocation of ATF4 was observed. We further demonstrated that ATF4 negatively regulates the expression of Tfam while promoting that of Glut1, which was responsible for the disruption of the metabolic shift to oxidative phosphorylation. Meanwhile, elevated levels of reactive oxygen species were observed in Lonp1 mutant cardiomyocytes. This study revealed that LONP1 safeguards metabolic shifts in the developing heart by controlling mitochondrial protein quality and implies that disrupted mitochondrial quality control may cause prenatal cardiomyopathy.

Keywords:  ATF4; Glycolysis; Heart development; LONP1; Metabolic shift; Mitochondrial quality control; Oxidative phosphorylation

DOI:  https://doi.org/10.1242/dev.200458
Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00160-5. [Epub ahead of print]82(5): 882-883

The case for brakes: Why restrain the size of Bax and Bak pores in outer mitochondrial membranes?

David W Andrews.

By comparing the structures of Bax and Bak megapores, Cosentino et al. (2022) reveal new insights suggesting the two pro-apoptotic proteins co-assemble into structures that release DNA from mitochondria and thereby trigger inflammation.

DOI: https://doi.org/10.1016/j.molcel.2022.02.022
Biomed Res Int. 2022 ;2022 7436577

Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.

Zhe Wang, Hai Bo, Yu Song, Can Li, Yong Zhang.

The mitochondrial unfolded protein response (UPRmt) can repair and remove misfolded or unfolded proteins in mitochondria and enhance mitochondrial protein homeostasis. Reactive oxygen species (ROS) produced by regular exercise is a crucial signal for promoting health, and skeletal muscle mitochondria are the primary source of ROS during exercise. To verify whether UPRmt is related to ROS produced by mitochondria in skeletal muscle during regular exercise, we adapted MitoTEMPO, mitochondrially targeted antioxidants, and ROS production by mitochondria. Our results showed that mitochondrial ROS is the key factor for activating UPRmt in different pathways.

DOI: https://doi.org/10.1155/2022/7436577
Nat Neurosci. 2022 Mar 03.

Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.

Omar Mossad, Bérénice Batut, Bahtiyar Yilmaz, Nikolaos Dokalis, Charlotte Mezö, Elisa Nent, Lara Susann Nabavi, Melanie Mayer, Feres José Mocayar Maron, Joerg M Buescher, Mercedes Gomez de Agüero, Antal Szalay, Tim Lämmermann, Andrew J Macpherson, Stephanie C Ganal-Vonarburg, Rolf Backofen, Daniel Erny, Marco Prinz, Thomas Blank.

Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.

DOI: https://doi.org/10.1038/s41593-022-01027-3
Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00108-3. [Epub ahead of print]82(5): 1066-1077.e7

MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.

Sotirios D Zervopoulos, Aristeidis E Boukouris, Bruno Saleme, Alois Haromy, Saymon Tejay, Gopinath Sutendra, Evangelos D Michelakis.

  The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points. A decrease in nuclear MFN2 levels decreases mitochondria tethering and nPDC levels. Mitochondrial PDC crosses the NE and interacts with lamin A, forming a ring below the NE before crossing through the lamin layer into the nucleoplasm, in areas away from NPCs. Effective blockage of NPC trafficking does not decrease nPDC levels. The PDC-lamin interaction is maintained during cell division, when lamin depolymerizes and disassembles before reforming daughter nuclear envelopes, providing another pathway for nPDC entry during mitosis. Our work provides a different angle to understanding mitochondria-to-nucleus communication and nuclear metabolism.

Keywords:  acetylation; cell cycle; lamin; metabolism; mitochondria; mitofusin; nucleus; protein trafficking; pyruvate dehydrogenase complex; tethering

DOI:  https://doi.org/10.1016/j.molcel.2022.02.003
Neurochem Res. 2022 Feb 28.

Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains.

Pulleri Kandi Harsha, Sathyanarayanan Ranganayaki, Gowri Yale, Gourav Dey, Kiran K Mangalaparthi, Anusha Yarlagadda, B K Chandrasekhar Sagar, Anita Mahadevan, M M Srinivas Bharath, Reeta S Mani.

  Rabies is a fatal encephalitis caused by the Rabies lyssavirus (RABV). The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome. The role of mitochondrial changes has been suggested as a possible mechanism for neuronal dysfunction in rabies. However, these findings are mostly based on studies that have employed experimental models and laboratory-adapted virus. Studies on brain tissues from naturally infected human and animal hosts are lacking. The current study investigated the role of mitochondrial changes in rabies by morphological, biochemical and proteomic analysis of RABV-infected human and canine brains. Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains. Proteomic analysis revealed involvement of mitochondrial processes (oxidative phosphorylation, cristae formation, homeostasis and transport), synaptic proteins and autophagic pathways, with over-expression of subunits of mitochondrial respiratory complexes. Consistent with these findings, human and canine brains displayed elevated activities of complexes I (p < 0.05), IV (p < 0.05) and V (p < 0.05). However, this did not result in elevated ATP production (p < 0.0001), probably due to lowered mitochondrial membrane potential as noted in RABV-infected cells in culture. These could lead to mitochondrial dysfunction and mitophagy as indicated by expression of FKBP8 (p < 0.05) and PINK1 (p < 0.001)/PARKIN (p > 0.05) and ensuing autophagy, as shown by the status of LCIII (p < 0.05), LAMP1 (p < 0.001) and pertinent ultrastructural markers. We propose that altered mitochondrial bioenergetics and cristae architecture probably induce mitophagy, leading to autophagy and consequent neuronal dysfunction in rabies.

Keywords:  Mitochondria; Neuronal dysfunction; Proteomics; Rabies

DOI:  https://doi.org/10.1007/s11064-022-03556-6
Autophagy. 2022 Feb 27. 1-12

Autophagy deficiency abolishes liver mitochondrial DNA segregation.

Katiane Tostes, Angélica C Dos Santos, Lindomar O Alves, Luiz R G Bechara, Rachel Marascalchi, Carolina H Macabelli, Mateus P Grejo, William T Festuccia, Roberta A Gottlieb, Julio C B Ferreira, Marcos R Chiaratti.

  Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.

Keywords:  Atg7; NZB; heteroplasmy; mitochondria; mitophagy; parkin

DOI:  https://doi.org/10.1080/15548627.2022.2038501
Transl Psychiatry. 2022 Feb 28. 12(1): 87

Metabolomic signature and mitochondrial dynamics outline the difference between vulnerability and resilience to chronic stress.

Paola Brivio, Matteo Audano, Maria Teresa Gallo, Piotr Gruca, Magdalena Lason, Ewa Litwa, Fabio Fumagalli, Mariusz Papp, Nico Mitro, Francesca Calabrese.

Stress is the foremost environmental factor involved in the pathophysiology of major depressive disorder (MDD). However, individual differences among people are critical as some people exhibit vulnerability while other are resilient to repeated exposure to stress. Among the others, a recent theory postulates that alterations of energy metabolism might contribute to the development of psychopathologies. Here we show that the bioenergetic status in the ventral hippocampus (vHip), a brain subregion tightly involved in the regulation of MDD, defined the development of vulnerability or resilience following two weeks of chronic mild stress. Among the different metabolomic signatures observed, the glycolysis and tricarboxylic acid cycle may be specifically involved in defining vulnerability, revealing a previously unappreciated mechanism of sensitivity to stress. These findings point to mitochondrial morphology and recycling as critical in the ability to cope with stress. We show that vulnerable rats favor mitochondrial fusion to counteract the overproduction of reactive oxidative species whereas resilient rats activate fission to guarantee metabolic efficiency. Our results indicate that the modulation of the energetic metabolite profile in vHip under chronic stress exposure may represent a mechanism to explain the difference between vulnerable and resilient rats, unraveling novel and promising targets for specific therapeutic interventions.

DOI: https://doi.org/10.1038/s41398-022-01856-7
Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00119-8. [Epub ahead of print]82(5): 886-888

Bypassing the nuclear gate: A non-canonical entry pathway for the mitochondrial pyruvate dehydrogenase complex.

Emily Boyle, Florian Wilfling.

Zervopoulos et al. (2022) propose a non-canonical nuclear import pathway for the functional mitochondrial pyruvate dehydrogenase complex (PDC), facilitated by dynamic MFN2-mediated tethering of mitochondria to the nuclear envelope upon exposure to proliferative stimuli.

DOI: https://doi.org/10.1016/j.molcel.2022.02.014
PLoS Biol. 2022 Mar;20(3): e3001558

A common evolutionary origin reveals fundamental principles of protein insertases.

F-Nora Vögtle, Hans-Georg Koch, Chris Meisinger.

Membrane proteins require protein machineries to insert their hydrophobic transmembrane domains (TMDs) into the lipid bilayer. A functional analysis of protein insertases in this issue of PLOS Biology reveals that the fundamental mechanism of membrane protein insertion is universally conserved.

DOI: https://doi.org/10.1371/journal.pbio.3001558