bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒11‒20
eighteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.
  2. LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-κB to the nucleus.
  3. LUBAC and NF-κB trigger a nuclear response from mitochondria.
  4. Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
  5. OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
  6. Elucidation of the Role of FAM210B in Mitochondrial Metabolism and Erythropoiesis.
  7. Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner.
  8. Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization.
  9. Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis.
  10. The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy.
  11. BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia.
  12. Mitochondria dysfunction impairs Tribolium castaneum wing development during metamorphosis.
  13. A BAK subdomain that binds mitochondrial lipids selectively and releases cytochrome C.
  14. Alternative respiratory oxidases to study the animal electron transport chain.
  15. Nonstop mRNAs generate a ground state of mitochondrial gene expression noise.
  16. Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma.
  17. Mechanism and regulation of mitophagy in nonalcoholic fatty liver disease (NAFLD): A mini-review.
  18. AAA+ proteases: the first line of defense against mitochondrial damage.
  1. Proc Natl Acad Sci U S A. 2022 Nov 22. 119(47): e2210730119
    Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.
    Takaya Ishihara, Reiko Ban-Ishihara, Azusa Ota, Naotada Ishihara.
      Mitochondria have their own DNA (mtDNA), which encodes essential respiratory subunits. Under live imaging, mitochondrial nucleoids, composed of several copies of mtDNA and DNA-binding proteins, such as mitochondrial transcription factor A (TFAM), actively move inside mitochondria and change the morphology, in concert with mitochondrial membrane fission. Here we found the mitochondrial inner membrane-anchored AAA-ATPase protein ATAD3A mediates the nucleoid dynamics. Its ATPase domain exposed to the matrix binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also required ATAD3A oligomerization via an interaction between the coiled-coil domains in intermembrane space. In ATAD3A deficiency, impaired nucleoid trafficking repressed the clustered and enlarged nucleoids observed in mitochondrial fission-deficient cells resulted in dispersed distribution of small nucleoids observed throughout the mitochondrial network, and this enhanced respiratory complex formation. Thus, mitochondrial fission and nucleoid trafficking cooperatively determine the size, number, and distribution of nucleoids in mitochondrial network, which should modulate respiratory complex formation.
    Keywords:  ATAD3A; Drp1; mitochondrial fission; mtDNA nucleoid; respiratory complex
    DOI:  https://doi.org/10.1073/pnas.2210730119
  2. EMBO J. 2022 Nov 18. e112006
    LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-κB to the nucleus.
    Zhixiao Wu, Lena A Berlemann, Verian Bader, Dominik A Sehr, Eva Dawin, Alberto Covallero, Jens Meschede, Lena Angersbach, Cathrin Showkat, Jonas B Michaelis, Christian Münch, Bettina Rieger, Dmitry Namgaladze, Maria Georgina Herrera, Fabienne C Fiesel, Wolfdieter Springer, Marta Mendes, Jennifer Stepien, Katalin Barkovits, Katrin Marcus, Albert Sickmann, Gunnar Dittmar, Karin B Busch, Dietmar Riedel, Marisa Brini, Jörg Tatzelt, Tito Cali, Konstanze F Winklhofer.
      Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling; however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here, we show that the NF-κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-κB to the nucleus. TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF-mediated NF-κB activation, both serving as a signaling platform, as well as a transport mode for activated NF-κB to the nuclear.
    Keywords:  HOIP; NEMO; OTULIN; PINK1; ubiquitin
    DOI:  https://doi.org/10.15252/embj.2022112006
  3. EMBO J. 2022 Nov 18. e112920
    LUBAC and NF-κB trigger a nuclear response from mitochondria.
    Junsheng Chen, Thomas Simmen.
      Mitochondria are key signaling hubs for innate immune responses. In this issue, Wu et al (2022) report that remodeling of the outer mitochondrial membrane by the linear ubiquiting chain assembly complex (LUBAC) facilitates transport of activated NF-κB to the nucleus in response to TNF signaling.
    DOI:  https://doi.org/10.15252/embj.2022112920
  4. J Cell Biol. 2023 Jan 02. pii: e202203019. [Epub ahead of print]222(1):
    Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
    Olesia Ignatenko, Satu Malinen, Sofiia Rybas, Helena Vihinen, Joni Nikkanen, Aleksander Kononov, Eija S Jokitalo, Gulayse Ince-Dunn, Anu Suomalainen.
      Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.
    DOI:  https://doi.org/10.1083/jcb.202203019
  5. Sci Immunol. 2022 Nov 25. 7(77): eabm8182
    OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
    Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis.
      T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in TH17s. We found that TH17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS TH17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS TH17s. By contrast, glycolytic TH17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected TH17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.abm8182
  6. Mol Cell Biol. 2022 Nov 14. e0014322
    Elucidation of the Role of FAM210B in Mitochondrial Metabolism and Erythropoiesis.
    Chie Suzuki, Tohru Fujiwara, Hiroki Shima, Koya Ono, Kei Saito, Hiroki Kato, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Yasushi Onishi, Hisayuki Yokoyama, Yukio Nakamura, Kazuhiko Igarashi, Hideo Harigae.
      Mitochondria play essential and specific roles during erythroid differentiation. Recently, FAM210B, encoding a mitochondrial inner membrane protein, has been identified as a novel target of GATA-1, as well as an erythropoietin-inducible gene. While FAM210B protein is involved in regulate mitochondrial metabolism and heme biosynthesis, its detailed function remains unknown. Here, we generated both knockout and knockdown of endogenous FAM210B in human induced pluripotent stem-derived erythroid progenitor (HiDEP) cells using CRISPR/Cas9 methodology. Intriguingly, erythroid differentiation was more pronounced in the FAM210B-depleted cells, and this resulted in increased frequency of orthochromatic erythroblasts and decreased frequencies of basophilic/polychromatic erythroblasts. Comprehensive metabolite analysis and functional analysis indicated that oxygen consumption rates and the NAD (NAD+)/NADH ratio were significantly decreased, while lactate production was significantly increased in FAM210B deletion HiDEP cells, indicating involvement of FAM210B in mitochondrial energy metabolism in erythroblasts. Finally, we purified FAM210B-interacting protein from K562 cells that stably expressed His/biotin-tagged FAM210B. Mass spectrometry analysis of the His/biotin-purified material indicated interactions with multiple subunits of mitochondrial ATP synthases, such as subunit alpha (ATP5A) and beta (ATP5B). Our results suggested that FAM210B contributes prominently to erythroid differentiation by regulating mitochondrial energy metabolism. Our results provide insights into the pathophysiology of dysregulated hematopoiesis.
    Keywords:  FAM210B; erythroid differentiation; mitochondria; mitochondrial ATP synthase
    DOI:  https://doi.org/10.1128/mcb.00143-22
  7. iScience. 2022 Nov 18. 25(11): 105410
    Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner.
    Christine E Robbins, Bhumil Patel, Danielle L Sawyer, Barrie Wilkinson, Brian K Kennedy, Mark A McCormick.
      Deletion of genes encoding ribosomal proteins extends lifespan in yeast. This increases translation of the functionally conserved transcription factor Gcn4, and lifespan extension in these mutants is GCN4-dependent. Gcn4 is also translationally upregulated by uncharged tRNAs, as are its C aenorhabditis elegans and mammalian functional orthologs. Here, we show that cytosolic tRNA synthetase inhibitors upregulate Gcn4 translation and extend yeast lifespan in a Gcn4-dependent manner. This cytosolic tRNA synthetase inhibitor is also able to extend the lifespan of C. elegans in an atf-4-dependent manner. We show that mitochondrial tRNA synthetase inhibitors greatly extend the lifespan of C. elegans, and this depends on atf-4. This suggests that perturbations of both cytosolic and mitochondrial translation may act in part via the same downstream pathway. These findings establish GCN4 orthologs as conserved longevity factors and, as long-lived mice exhibit elevated ATF4, leave open the possibility that tRNA synthetase inhibitors could also extend lifespan in mammals.
    Keywords:  Biochemistry; Biological sciences; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105410
  8. iScience. 2022 Nov 18. 25(11): 105447
    Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization.
    M A Neginskaya, S E Morris, E V Pavlov.
      An increase in permeability of the mitochondrial inner membrane, mitochondrial permeability transition (PT), is the central event responsible for cell death and tissue damage in conditions such as stroke and heart attack. PT is caused by the cyclosporin A (CSA)-dependent calcium-induced pore, the permeability transition pore (PTP). The molecular details of PTP are incompletely understood. We utilized holographic and fluorescent microscopy to assess the contribution of ATP synthase and adenine nucleotide translocator (ANT) toward PTP. In cells lacking either ATP synthase or ANT, we observed CSA-sensitive membrane depolarization, but not high-conductance PTP. In wild-type cells, calcium-induced CSA-sensitive depolarization preceded opening of PTP, which occurred only after nearly complete mitochondrial membrane depolarization. We propose that both ATP synthase and ANT are required for high-conductance PTP but not depolarization, which presumably occurs through activation of the low-conductance PT, which has a molecular nature that is different from both complexes.
    Keywords:  Cell biology; Functional aspects of cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105447
  9. Cancer Res Commun. 2022 Oct 10. 2(10): 1144-1161
    Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis.
    Yoshimi Endo Greer, Lidia Hernandez, Emily M J Fennell, Manjari Kundu, Donna Voeller, Raj Chari, Samuel F Gilbert, Thomas S K Gilbert, Shashikala Ratnayake, Binwu Tang, Markus Hafner, Qingrong Chen, Daoud Meerzaman, Edwin Iwanowicz, Christina M Annunziata, Lee M Graves, Stanley Lipkowitz.
      Mitochondria are multifaceted organelles which are important for bioenergetics, biosynthesis and signaling in metazoans. Mitochondrial functions are frequently altered in cancer to promote both the energy and the necessary metabolic intermediates for biosynthesis required for tumor growth. Cancer stem cells (CSCs) contribute to chemotherapy resistance, relapse, and metastasis. Recent studies have shown that while non-stem, bulk cancer cells utilize glycolysis, breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and therefore targeting mitochondria may inhibit CSC function. We previously reported that small molecule ONC201, which is an agonist for the mitochondrial caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer cells. In this study, we report that ClpP agonists inhibit breast cancer cell proliferation and CSC function in vitro and in vivo. Mechanistically, we found that OxPhos inhibition downregulates multiple pathways required for CSC function, such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists showed significantly greater inhibitory effect on CSC functions compared with other mitochondria-targeting drugs. Further studies showed that ClpP agonists deplete NAD(P)+ and NAD(P)H, induce redox imbalance, dysregulate one-carbon metabolism and proline biosynthesis. Downregulation of these pathways by ClpP agonists further contribute to the inhibition of CSC function. In conclusion, ClpP agonists inhibit breast CSC functions by disrupting mitochondrial homeostasis in breast cancer cells and inhibiting multiple pathways critical to CSC function.Significance: ClpP agonists disrupt mitochondrial homeostasis by activating mitochondrial matrix protease ClpP. We report that ClpP agonists inhibit cell growth and cancer stem cell functions in breast cancer models by modulating multiple metabolic pathways essential to cancer stem cell function.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0142
  10. J Biol Chem. 2022 Nov 12. pii: S0021-9258(22)01147-4. [Epub ahead of print] 102704
    The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy.
    Shan Sun, Hongyu Hou, Guoqiang Ma, Qilian Ma, Ningning Li, Li Zhang, Chunsheng Dong, Mian Cao, Kin Yip Tam, Zheng Ying, Hongfeng Wang.
      The autophagic clearance of mitochondria has been defined as mitophagy, which is triggered by mitochondrial damage and serves as a major pathway for mitochondrial homeostasis and cellular quality control. PINK1 and Parkin-mediated mitophagy is the most extensively studied form of mitophagy, which has been linked to the pathogenesis of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current paradigm of this particular mitophagy pathway is that the ubiquitination of the outer mitochondrial membrane is the key step to enable the recognition of damaged mitochondria by the core autophagic component autophagosome. However, whether the inner mitochondrial membrane (IMM) is ubiquitinated by Parkin and its contribution to sufficient mitophagy remain unclear. Here, using molecular, cellular, and biochemical approaches, we report that prohibitin 2 (PHB2), an essential IMM receptor for mitophagy, is ubiquitinated by Parkin and thereby gains higher affinity to the autophagosome during mitophagy. Our findings suggest that Parkin directly binds to PHB2 through its RING1 domain and promotes K11- and K33-linked ubiquitination on K142/K200 sites of PHB2, thereby enhancing the interaction between PHB2 and MAP1LC3B/LC3B. Interestingly and importantly, our study allows us to propose a novel model in which IMM protein PHB2 serves as both a receptor and a ubiquitin-mediated base for autophagosome recruitment to ensure efficient mitophagy.
    Keywords:  MAP1LC3B/LC3B; PHB2; Parkin; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2022.102704
  11. Cell Death Dis. 2022 Nov 17. 13(11): 966
    BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia.
    Yun-Ling He, Jian Li, Sheng-Hui Gong, Xiang Cheng, Ming Zhao, Yan Cao, Tong Zhao, Yong-Qi Zhao, Ming Fan, Hai-Tao Wu, Ling-Ling Zhu, Li-Ying Wu.
      Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3), a mitochondrial outer membrane protein, is a mitophagy receptor that mediates mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 (c-Jun N-terminal kinase 1/2) phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating the direct binding of BNIP3 to LC3 (microtubule-associated protein 1 light chain 3), while PP1/2A (protein phosphatase 1/2A) represses mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.
    DOI:  https://doi.org/10.1038/s41419-022-05418-z
  12. Commun Biol. 2022 Nov 15. 5(1): 1252
    Mitochondria dysfunction impairs Tribolium castaneum wing development during metamorphosis.
    Yaoyu Jiao, Subba Reddy Palli.
      The disproportionate growth of insect appendages such as facultative growth of wings and exaggeration of beetle horns are examples of phenotypic plasticity. Insect metamorphosis is the critical stage for development of pupal and adult structures and degeneration of the larval cells. How the disproportionate growth of external appendages is regulated during tissue remodeling remains unanswered. Tribolium castaneum is used as a model to study the function of mitochondria in metamorphosis. Mitochondrial dysfunction is achieved by the knockdown of key mitochondrial regulators. Here we show that mitochondrial function is not required for metamorphosis except that severe mitochondrial dysfunction blocks ecdysis. Surprisingly, various abnormal wing growth, including short and wingless phenotypes, are induced after knocking down mitochondrial regulators. Mitochondrial activity is regulated by IIS (insulin/insulin-like growth factor signaling)/FOXO (forkhead box, sub-group O) pathway through TFAM (transcription factor A, mitochondrial). RNA sequencing and differential gene expression analysis show that wing-patterning and insect hormone response genes are downregulated, while programmed cell death and immune response genes are upregulated in insect wing discs with mitochondrial dysfunction. These studies reveal that mitochondria play critical roles in regulating insect wing growth by targeting wing development during metamorphosis, thus showing a novel molecular mechanism underlying developmental plasticity.
    DOI:  https://doi.org/10.1038/s42003-022-04185-z
  13. Cell Death Differ. 2022 Nov 14.
    A BAK subdomain that binds mitochondrial lipids selectively and releases cytochrome C.
    Haiming Dai, Kevin L Peterson, Karen S Flatten, X Wei Meng, Annapoorna Venkatachalam, Cristina Correia, Marina Ramirez-Alvarado, Yuan-Ping Pang, Scott H Kaufmann.
      How BAK and BAX induce mitochondrial outer membrane (MOM) permeabilization (MOMP) during apoptosis is incompletely understood. Here we have used molecular dynamics simulations, surface plasmon resonance, and assays for membrane permeabilization in vitro and in vivo to assess the structure and function of selected BAK subdomains and their derivatives. Results of these studies demonstrate that BAK helical regions α5 and α6 bind the MOM lipid cardiolipin. While individual peptides corresponding to these helical regions lack the full biological activity of BAK, tandem peptides corresponding to α4-α5, α5-α6, or α6-α7/8 can localize exogenous proteins to mitochondria, permeabilize liposomes composed of MOM lipids, and cause MOMP in the absence of the remainder of the BAK protein. Importantly, the ability of these tandem helices to induce MOMP under cell-free conditions is diminished by mutations that disrupt the U-shaped helix-turn-helix structure of the tandem peptides or decrease their lipid binding. Likewise, BAK-induced apoptosis in intact cells is diminished by CLS1 gene interruption, which decreases mitochondrial cardiolipin content, or by BAK mutations that disrupt the U-shaped tandem peptide structure or diminish lipid binding. Collectively, these results suggest that BAK structural rearrangements during apoptosis might mobilize helices involved in specific protein-lipid interactions that are critical for MOMP.
    DOI:  https://doi.org/10.1038/s41418-022-01083-z
  14. Biochim Biophys Acta Bioenerg. 2022 Nov 14. pii: S0005-2728(22)00406-6. [Epub ahead of print] 148936
    Alternative respiratory oxidases to study the animal electron transport chain.
    Pablo Hernansanz-Agustín, José Antonio Enríquez.
      Oxidative phosphorylation is a common process to most organisms in which the main function is to generate an electrochemical gradient across the inner mitochondrial membrane (IMM) and to make energy available to the cell. However, plants, many fungi and some animals maintain non-energy conserving oxidases which serve as a bypass to coupled respiration. Namely, the alternative NADH:ubiquinone oxidoreductase NDI1, present in the complex I (CI)-lacking Saccharomyces cerevisiae, and the alternative oxidase, ubiquinol:oxygen oxidoreductase AOX, present in many organisms across different kingdoms. In the last few years, these alternative oxidases have been used to dissect previously indivisible processes in bioenergetics and have helped to discover, understand, and corroborate important processes in mitochondria. Here, we review how the use of alternative oxidases have contributed to the knowledge in CI stability, bioenergetics, redox biology, and the implications of their use in current and future research.
    Keywords:  AOX; Alternative oxidase; CoQ pool; Oxphos; ROS
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148936
  15. Sci Adv. 2022 Nov 16. 8(46): eabq5234
    Nonstop mRNAs generate a ground state of mitochondrial gene expression noise.
    Kah Ying Ng, Guleycan Lutfullahoglu Bal, Uwe Richter, Omid Safronov, Lars Paulin, Cory D Dunn, Ville O Paavilainen, Julie Richer, William G Newman, Robert W Taylor, Brendan J Battersby.
      A stop codon within the mRNA facilitates coordinated termination of protein synthesis, releasing the nascent polypeptide from the ribosome. This essential step in gene expression is impeded with transcripts lacking a stop codon, generating nonstop ribosome complexes. Here, we use deep sequencing to investigate sources of nonstop mRNAs generated from the human mitochondrial genome. We identify diverse types of nonstop mRNAs on mitochondrial ribosomes that are resistant to translation termination by canonical release factors. Failure to resolve these aberrations by the mitochondrial release factor in rescue (MTRFR) imparts a negative regulatory effect on protein synthesis that is associated with human disease. Our findings reveal a source of underlying noise in mitochondrial gene expression and the importance of responsive ribosome quality control mechanisms for cell fitness and human health.
    DOI:  https://doi.org/10.1126/sciadv.abq5234
  16. Mitochondrion. 2022 Nov 09. pii: S1567-7249(22)00090-3. [Epub ahead of print]68 10-14
    Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma.
    Samir P Patel, Felicia M Michael, Jenna L Gollihue, W Brad Hubbard, Patrick G Sullivan, Alexander G Rabchevsky.
      Herein, we review evidence that targeting mitochondrial dysfunction with 'mitoceuticals' is an effective neuroprotective strategy following neurotrauma, and that isolated exogenous mitochondria can be effectively transplanted into host spinal cord parenchyma to increase overall cellular metabolism. We further discuss control measures to ensure greatest potential for mitochondrial transfer, notably using erodible thermogelling hydrogels to deliver respiratory competent mitochondria to the injured spinal cord.
    Keywords:  Bioenergetics; Hydrogel; Metabolism; Mitochondria; Oxidative phosphorylation; Spinal cord; Transplantation
    DOI:  https://doi.org/10.1016/j.mito.2022.11.001
  17. Life Sci. 2022 Nov 10. pii: S0024-3205(22)00862-1. [Epub ahead of print] 121162
    Mechanism and regulation of mitophagy in nonalcoholic fatty liver disease (NAFLD): A mini-review.
    Lihui Zhu, Xiao Wu, Rongrong Liao.
      Mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of nonalcoholic fatty liver disease (NAFLD). Thus, maintenance of mitochondria homeostasis and function is important for NAFLD treatment. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, is beneficial for mitochondrial homeostasis. Notably, strategies that regulate mitophagy exert beneficial effects in preclinical experiments. Traditional Chinese medicine (TCM) is a natural product including active ingredients, extracts, and has great potential in the prevention and treatment of liver diseases. Given the importance of mitophagy, this review summarizes mitophagy-related pathways and the latest findings on the regulation of mitophagy in NAFLD. We also highlight the potential of TCM targeting mitophagy for the treatment of NAFLD.
    Keywords:  Autophagy; Fatty liver disease; Lipid; Metabolism; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.lfs.2022.121162
  18. PeerJ. 2022 ;10 e14350
    AAA+ proteases: the first line of defense against mitochondrial damage.
    Gautam Pareek.
      Mitochondria play essential cellular roles in Adenosine triphosphate (ATP) synthesis, calcium homeostasis, and metabolism, but these vital processes have potentially deadly side effects. The production of the reactive oxygen species (ROS) and the aggregation of misfolded mitochondrial proteins can lead to severe mitochondrial damage and even cell death. The accumulation of mitochondrial damage is strongly implicated in aging and several incurable diseases, including neurodegenerative disorders and cancer. To oppose this, metazoans utilize a variety of quality control strategies, including the degradation of the damaged mitochondrial proteins by the mitochondrial-resident proteases of the ATPase Associated with the diverse cellular Activities (AAA+) family. This mini-review focuses on the quality control mediated by the mitochondrial-resident proteases of the AAA+ family used to combat the accumulation of damaged mitochondria and on how the failure of this mitochondrial quality control contributes to diseases.
    Keywords:  AAA+ Protease; Mitochondria in neurological disorders; Mitochondrial Translation; Mitochondrial Unfolded Protein Response; Mitochondrial quality control
    DOI:  https://doi.org/10.7717/peerj.14350
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