bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2023–06–25
nine papers selected by
Omkar Joshi, Turku Bioscience
  1. Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
  2. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
  3. Structural basis of mitochondrial protein import by the TIM23 complex.
  4. PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
  5. LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function.
  6. FUNDC1 modulates mitochondrial defects and pancreatic β-cell dysfunction under lipotoxicity.
  7. Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
  8. Imaging of mtHyPer7, a Ratiometric Biosensor for Mitochondrial Peroxide, in Living Yeast Cells.
  9. Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.
  1. Science. 2023 Jun 23. 380(6651): eadh9351
    Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
    Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.
      In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.
    DOI:  https://doi.org/10.1126/science.adh9351
  2. bioRxiv. 2023 Apr 13. pii: 2023.04.13.536717. [Epub ahead of print]
    A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
    Sun Woo Sophie Kang, Rory P Cunningham, Colin B Miller, Constance M Cultraro, Jonathan Hernandez, Lisa M Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal (PP) and pericentral (PC) axis. How these mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combined intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We found that PP and PC mitochondria are morphologically and functionally distinct; beta-oxidation and mitophagy were elevated in PP regions, while lipid synthesis was predominant in the PC mitochondria. In addition, comparative phosphoproteomics revealed that mitophagy and lipid synthesis are regulated by phosphorylation in a zonated manner. Furthermore, we demonstrated that acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifted mitochondrial phenotypes in the PP and PC regions of the intact liver. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. The findings have important implications for liver physiology and disease.
    DOI:  https://doi.org/10.1101/2023.04.13.536717
  3. Nature. 2023 Jun 21.
    Structural basis of mitochondrial protein import by the TIM23 complex.
    Sue Im Sim, Yuanyuan Chen, Diane L Lynch, James C Gumbart, Eunyong Park.
      Mitochondria import nearly all of their approximately 1,000-2,000 constituent proteins from the cytosol across their double-membrane envelope1-5. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM23 complex, mediates import of presequence-containing proteins (preproteins) into the mitochondrial matrix and inner membrane. Among about ten different subunits of the TIM23 complex, the essential multipass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel6-11. However, the mechanism by which these subunits form a translocation path in the membrane and enable the import process remains unclear due to a lack of structural information. Here we determined the cryo-electron microscopy structure of the core TIM23 complex (heterotrimeric Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. Contrary to the prevailing model, Tim23 and Tim17 themselves do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Our structural and biochemical analyses show that the cavity of Tim17, but not Tim23, forms the protein translocation path, whereas Tim23 probably has a structural role. The results further suggest that, during translocation of substrate polypeptides, the nonessential subunit Mgr2 seals the lateral opening of the Tim17 cavity to facilitate the translocation process. We propose a new model for the TIM23-mediated protein import and sorting mechanism, a central pathway in mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s41586-023-06239-6
  4. EMBO Rep. 2023 Jun 19. e56399
    PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
    Felix Kraus, Ellen A Goodall, Ian R Smith, Yizhi Jiang, Julia C Paoli, Frank Adolf, Jiuchun Zhang, Joao A Paulo, Brenda A Schulman, J Wade Harper.
      The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support the recruitment of mitophagy receptors. The ubiquitin ligase substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed a role for FBXO7 in promoting Parkin-dependent mitophagy. Here, we systematically examine the involvement of FBXO7 in depolarization and mt UPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems. We find that FBXO7-/- cells have no demonstrable defect in: (i) kinetics of pUb accumulation, (ii) pUb puncta on mitochondria by super-resolution imaging, (iii) recruitment of Parkin and autophagy machinery to damaged mitochondria, (iv) mitophagic flux, and (v) mitochondrial clearance as quantified by global proteomics. Moreover, global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian-pyramidal syndrome.
    Keywords:  FBXO7; iNeurons; mitophagy; proteomics; ubiquitin ligase
    DOI:  https://doi.org/10.15252/embr.202256399
  5. Research (Wash D C). 2023 ;6 0175
    LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function.
    Yujie Li, Dawei Huang, Lianqun Jia, Fugen Shangguan, Shiwei Gong, Linhua Lan, Zhiyin Song, Juan Xu, Chaojun Yan, Tongke Chen, Yin Tan, Yongzhang Liu, Xingxu Huang, Carolyn K Suzuki, Zhongzhou Yang, Guanlin Yang, Bin Lu.
      Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.
    DOI:  https://doi.org/10.34133/research.0175
  6. Biochem Biophys Res Commun. 2023 Jun 14. pii: S0006-291X(23)00797-0. [Epub ahead of print]672 54-64
    FUNDC1 modulates mitochondrial defects and pancreatic β-cell dysfunction under lipotoxicity.
    Beier Tong, Zhengwei Zhang, Xuefeng Li, Jie Liu, Huawei Wang, Linyang Song, Jieyuan Feng, Zhe Dai, Yancheng Xu.
      Insulin resistance and many metabolic disorders are causally linked to mitochondrial dysfunction or defective mitochondrial quality control. Mitophagy is a highly selective mechanism that recognizes and removes damaged mitochondria to maintain mitochondrial homeostasis. Here, we addressed the potential role of FUNDC1, a mediator of mitophagy, in pancreatic β-cell dysfunction under lipotoxicity. In pancreatic MIN6 cells, FUNDC1 deficiency aggravated palmitate-induced mitochondrial dysfunction, which led to cell death and insulin insensitivity. Interestingly, FUNDC1 overexpression prevented these cellular harms brought on by palmitate. In mice models, pancreatic-specific FUNDC1 overexpression alleviated high-fat diet (HFD)-induced insulin resistance and obesity. Mechanistically, pancreatic-specific overexpression of FUNDC1 ameliorated mitochondrial defects and endoplasmic reticulum (ER) stress upon HFD. Our research indicates that FUNDC1 plays an essential role in apoptosis and dysfunction of pancreatic β-cells via modulating lipotoxicity-induced mitochondrial defects.
    Keywords:  FUNDC1; Insulin resistance; Mitochondrial dysfunction; Palmitate; Pancreatic β-cell
    DOI:  https://doi.org/10.1016/j.bbrc.2023.06.042
  7. Cell Mol Life Sci. 2023 Jun 20. 80(7): 183
    Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
    Lijun Chi, Dorothy Lee, Sharon Leung, Guanlan Hu, Bijun Wen, Paul Delgado-Olguin, Miluska Vissa, Ren Li, John H Brumell, Peter K Kim, Robert H J Bandsma.
      Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.
    Keywords:  Fenofibrate; Malnutrition; Metabolism; Mitophagy; Nuclear hormone receptor; mTOR
    DOI:  https://doi.org/10.1007/s00018-023-04827-3
  8. J Vis Exp. 2023 Jun 02.
    Imaging of mtHyPer7, a Ratiometric Biosensor for Mitochondrial Peroxide, in Living Yeast Cells.
    Emily Jie-Ning Yang, Istvan R Boldogh, Haojie Ji, Liza Pon, Theresa C Swayne.
      Mitochondrial dysfunction, or functional alteration, is found in many diseases and conditions, including neurodegenerative and musculoskeletal disorders, cancer, and normal aging. Here, an approach is described to assess mitochondrial function in living yeast cells at cellular and subcellular resolutions using a genetically encoded, minimally invasive, ratiometric biosensor. The biosensor, mitochondria-targeted HyPer7 (mtHyPer7), detects hydrogen peroxide (H2O2) in mitochondria. It consists of a mitochondrial signal sequence fused to a circularly permuted fluorescent protein and the H2O2-responsive domain of a bacterial OxyR protein. The biosensor is generated and integrated into the yeast genome using a CRISPR-Cas9 marker-free system, for more consistent expression compared to plasmid-borne constructs. mtHyPer7 is quantitatively targeted to mitochondria, has no detectable effect on yeast growth rate or mitochondrial morphology, and provides a quantitative readout for mitochondrial H2O2 under normal growth conditions and upon exposure to oxidative stress. This protocol explains how to optimize imaging conditions using a spinning-disk confocal microscope system and perform quantitative analysis using freely available software. These tools make it possible to collect rich spatiotemporal information on mitochondria both within cells and among cells in a population. Moreover, the workflow described here can be used to validate other biosensors.
    DOI:  https://doi.org/10.3791/65428
  9. Mol Cell Endocrinol. 2023 Jun 15. pii: S0303-7207(23)00145-4. [Epub ahead of print] 111994
    Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.
    Cuihua Huang, Lishan Huang, Qintao Huang, Lu Lin, Lijing Wang, Yubin Wu, Kejun Wu, Ruonan Gao, Xiaoying Liu, XiaoHong Liu, Liqin Qi, Libin Liu.
      Severe hypoglycemia is closely related to adverse cardiovascular outcomes in patients with diabetes; however, the specific mechanism remains unclear. We previously found that severe hypoglycemia aggravated myocardial injury and cardiac dysfunction in diabetic mice, and that the mechanism of damage was related to mitochondrial oxidative stress and dysfunction. Based on the key regulatory role of mitophagy in mitochondrial quality control, this study aimed to further explore whether the myocardial damage caused by severe hypoglycemia is related to insufficient mitophagy and to clarify their underlying regulatory relationship. After severe hypoglycemia, mitochondrial reactive oxygen species increased, mitochondrial membrane potential and ATP content decreased, and pathological mitochondrial damage was aggravated in the myocardium of diabetic mice. This was accompanied by decreased mitochondrial biosynthesis, increased fusion, and downregulated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy. Treating diabetic mice with the mitophagy activator and polyphenol metabolite urolithin A activated PINK1/Parkin-dependent mitophagy, reduced myocardial oxidative stress and mitochondrial damage associated with severe hypoglycemia, improved mitochondrial function, alleviated myocardial damage, and ultimately improved cardiac function. Thus, we provide insight into the prevention and treatment of diabetic myocardial injury caused by hypoglycemia to reduce adverse cardiovascular outcomes in patients with diabetes.
    Keywords:  Diabetes mellitus; Mitophagy; Myocardial injury; Severe hypoglycemia
    DOI:  https://doi.org/10.1016/j.mce.2023.111994
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