bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒12‒11
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
  2. A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
  3. Mitochondrial cristae architecture protects against mtDNA release and inflammation.
  4. Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
  5. Enteropathogenic Escherichia coli regulates host-cell mitochondrial morphology.
  6. The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
  7. Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.
  1. Neurobiol Dis. 2022 Dec 05. pii: S0969-9961(22)00333-3. [Epub ahead of print]176 105941
    DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
    Federica De Lazzari, Francesco Agostini, Nicoletta Plotegher, Michele Sandre, Elisa Greggio, Aram Megighian, Luigi Bubacco, Federica Sandrelli, Alexander J Whitworth, Marco Bisaglia.
      The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1β as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1β null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1β leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1β null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.
    Keywords:  Autophagy; DJ-1; Energy balance; Mitochondria; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.nbd.2022.105941
  2. Nat Biomed Eng. 2022 Dec 05.
    A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
    Pedro Silva-Pinheiro, Christian D Mutti, Lindsey Van Haute, Christopher A Powell, Pavel A Nash, Keira Turner, Michal Minczuk.
      The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.
    DOI:  https://doi.org/10.1038/s41551-022-00968-1
  3. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01657-6. [Epub ahead of print]41(10): 111774
    Mitochondrial cristae architecture protects against mtDNA release and inflammation.
    Baiyu He, Huatong Yu, Shanshan Liu, Huayun Wan, Song Fu, Siqi Liu, Jun Yang, Zihan Zhang, Huanwei Huang, Qi Li, Fengchao Wang, Zhaodi Jiang, Qinghua Liu, Hui Jiang.
      Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
    Keywords:  CP: Cell biology; CP: Molecular biology; MICOS; Metaxin2; OPA1; SAM; cGAS-STING; cristae architecture; inflammation; mtDNA release; type I interferon response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111774
  4. Exp Mol Med. 2022 Dec 06.
    Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
    Jong-Hyuk Lee, Mansoor Hussain, Edward W Kim, Shang-Jung Cheng, Anthony K L Leung, Nima Borhan Fakouri, Deborah L Croteau, Vilhelm A Bohr.
      PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD+-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.
    DOI:  https://doi.org/10.1038/s12276-022-00894-x
  5. Gut Microbes. 2022 Jan-Dec;14(1):14(1): 2143224
    Enteropathogenic Escherichia coli regulates host-cell mitochondrial morphology.
    Jennifer Lising Roxas, Shylaja Ramamurthy, Katie Cocchi, Ilga Rutins, Anusha Harishankar, Al Agellon, John Scott Wilbur, Gresa Sylejmani, Gayatri Vedantam, V K Viswanathan.
      The diarrheagenic pathogen enteropathogenic Escherichia coli is responsible for significant childhood mortality and morbidity. EPEC and related attaching-and-effacing (A/E) pathogens use a type III secretion system to hierarchically deliver effector proteins into host cells and manipulate epithelial structure and function. Subversion of host mitochondrial biology is a key aspect of A/E pathogen virulence strategy, but the mechanisms remain poorly defined. We demonstrate that the early-secreted effector EspZ and the late-secreted effector EspH have contrasting effects on host mitochondrial structure and function. EspZ interacts with FIS1, a protein that induces mitochondrial fragmentation and mitophagy. Infection of epithelial cells with either wildtype EPEC or an isogenic espZ deletion mutant (ΔespZ) robustly upregulated FIS1 abundance, but a marked increase in mitochondrial fragmentation and mitophagy was seen only in ΔespZ-infected cells. FIS1-depleted cells were protected against ΔespZ-induced fission, and EspZ-expressing transfected epithelial cells were protected against pharmacologically induced mitochondrial fission and membrane potential disruption. Thus, EspZ interacts with FIS1 and blocks mitochondrial fragmentation and mitophagy. In contrast to WT EPEC, ΔespH-infected epithelial cells had minimal FIS1 upregulation and exhibited hyperfused mitochondria. Consistent with the contrasting impacts on organelle shape, mitochondrial membrane potential was preserved in ΔespH-infected cells, but profoundly disrupted in ΔespZ-infected cells. Collectively, our studies reveal hitherto unappreciated roles for two essential EPEC virulence factors in the temporal and dynamic regulation of host mitochondrial biology.
    Keywords:  EPEC; Enteropathogenic Escherichia coli; EspH; EspZ; FIS1; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1080/19490976.2022.2143224
  6. Nat Commun. 2022 Dec 08. 13(1): 7576
    The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
    Guanlan Hu, Catriona Ling, Lijun Chi, Mehakpreet K Thind, Samuel Furse, Albert Koulman, Jonathan R Swann, Dorothy Lee, Marjolein M Calon, Celine Bourdon, Christian J Versloot, Barbara M Bakker, Gerard Bryan Gonzales, Peter K Kim, Robert H J Bandsma.
      Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.
    DOI:  https://doi.org/10.1038/s41467-022-35317-y
  7. J Clin Invest. 2022 Dec 08. pii: e159498. [Epub ahead of print]
    Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.
    Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S Olson, Jennifer Davis, Rong Tian.
      Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is markedly impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a novel role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.
    Keywords:  Cardiology; Cardiovascular disease; Macrophages; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI159498
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